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)

Using a PCR-based cloning technique, we have isolated a series of DNA fragments coding for tyrosine kinases that are expressed in a metastatic human colon tumor, and have subsequently analyzed their expression pattern at the protein level in human tumors. We identified both the alpha and the beta forms of the platelet-derived growth factor receptor (PDGFR), axl and 8 other genes, including 3 cytoplasmic tyrosine kinases. To study their expression in human colon cancer, we performed Western blots of matched sets of normal tissues and of carcinomas from the same patient. These revealed that the alpha-PDGFR migrates predominantly as a 200-kDa band in 8/8 normal tissues, and as a 170-kDa band in 17/17 malignant tissues, as well as in colonic polyps, suggesting that expression of an isoform of this receptor may be a marker for the progression of colon cancer. Additional studies showed that the Axl receptor tyrosine kinase was expressed at 10-fold higher levels in a peritoneal metastatic nodule than in other normal and malignant tissues. Immunohistochemistry revealed Axl over-expression specifically in the malignant cells of the tumor. This indicates that over-expression and possibly a differential processing event of tyrosine kinase receptors may be involved in colon cancer, and that they are potential markers for the progression of this disease.
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PMID:Receptor tyrosine kinases expressed in metastatic colon cancer. 789 47

A series of 36 nitrothiophene tyrphostins were synthesized, 32 of which were novel structures. Their ability to inhibit the epidermal growth factor (EGF) receptor tyrosine kinase was assessed in a cell-free assay. Compounds containing a dinitrile, 2-aminoethene-1, 1-dinitrile or a thioamide group were good inhibitors of the receptor tyrosine kinase. Although anti-proliferative and cytotoxic activity was seen, no evidence of inhibition of EGF receptor autophosphorylation in intact cells was observed. The compounds showed no preferential inhibition of EGF-dependent proliferation of fibroblasts transfected with the EGF receptor. Furthermore, in a panel of squamous cell carcinoma cell lines with varying levels of EGF receptor expression, there was no selective cell kill of lines with the highest EGF receptor expression. The 2-nitro-5-substituted-thiophenes and the 2-nitro-3-substituted-thiophenes showed reduction potentials falling within the range likely to be reduced by cellular reducing agents, while the 2-nitro-4-substituted-thiophenes and 4-nitro-2-substituted-thiophenes did not. Compounds from the 2-nitro-5-substituted-thiophene series were shown to induce DNA damage, while no evidence of DNA damage was demonstrated with compounds from the 2-nitro-4-substituted-thiophene series. The 2-nitro-5-substituted-thiophene compound 4 showed significant tumour-type selectivity in the US National Cancer Institute human tumour cell line panel. The leukaemia cell lines were particularly sensitive to the compound, as were the majority of the colon cancer, melanoma and breast cancer cell lines, while the central nervous system-derived lines and the non-small cell lung cancer lines were particularly resistant. Further work is required to determine the precise mechanisms involved in these effects.
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PMID:Synthesis and biological evaluation of a series of tyrphostins containing nitrothiophene moieties as possible epidermal growth factor receptor tyrosine kinase inhibitors. 867 52

HTK is a receptor tyrosine kinase that belongs to the Eph subfamily. An extensive screening using BIAcore system revealed that a colon cancer cell line, C-1, expressed the ligand for HTK. From the conditioned medium of C-1 cells, a soluble form of ligand was purified by receptor affinity chromatography, and the isolation of full-length cDNA revealed that this ligand is identical to the human HTK ligand (HTKL) previously reported. HTK receptor tyrosine phosphorylation was induced by membrane-bound or clustered soluble HTKL but not by unclustered soluble HTKL, indicating that HTKL requires cell-to-cell interaction for receptor activation. Binding analysis demonstrated that HTKL binds to HTK with a much higher affinity (Kd: 1.23 nM) than the other transmembrane-type ligand for Eph family, LERK-2/ELKL (Kd: 135 nM). The expression of HTK in cord blood cells was upregulated after the culture in the presence of stem cell factor. Clustered soluble HTKL stimulated the proliferation of sorted HTK+ cord blood cells and a hematopoietic cell line, UT-7/EPO from which HTK was isolated. These findings suggest the involvement of HTK-HTKL system in the proliferation of HTK+ hematopoietic progenitor cells in the hematopoietic environment.
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PMID:Characterization of a ligand for receptor protein-tyrosine kinase HTK expressed in immature hematopoietic cells. 876 3

Colon carcinoma is the most common tumor of the gastrointestinal tract. According to some investigators, insulin, epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) man be involved in the neoplastic proliferation. Insulin-binding and receptor tyrosine kinase activity were investigated in colon carcinomas and in normal colons. The insulin receptor concentration, as shown by binding assays, was 17.4 +/- 4.3 fmol/micrograms in normal colon and 29.69 +/- 9.4 fmol/micrograms in colon carcinoma. Nevertheless, the insulin affinity of the receptor was similar in both groups (Kd identical to 1 nM). Both normal and neoplastic colon showed phosphorylation of the insulin receptor. The electrophoretic migration of the beta-subunit of the insulin receptors purified from colon carcinomas was similar to that of normal colon and both tissues demonstrated an insulin-dependent autophosphorylation. The receptor tyrosine kinase activity was measured by the incorporation of [gamma 32P]ATP into the beta-subunit. The basal and the insulin-stimulated tyrosine kinase activities were significantly higher in colon carcinomas compared to normal colon tissues (2.2 and 1.6 times, respectively). Understanding the metabolism of neoplastic cells may contribute to the development of prevention strategies as well as new therapies. It is now necessary to study other steps of the insulin signal transduction pathway, such as insulin receptor substrate 1 phosphorylation.
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PMID:Insulin receptor tyrosine kinase activity in colon carcinoma. 922 17

Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons. TRKA, a receptor tyrosine kinase cloned from a human colon cancer was later found to be expressed in the nervous system and phosphorylated in response to NGF. Somatic rearrangement(s) of the TRKA gene (also designated NTRK1) are responsible for formation of some oncogenes. Genetic defects in TRKA are responsible for a human disorder, congenital insensitivity to pain with anhidrosis (CIPA). We report here isolation and characterization of the TRKA gene which spans at least 23 kb and is split into 17 exons. Exon sizes range from 18 to 394 bp and intron sizes range from 170 bp to at least 3.3 kb. Sizes and boundaries of the exons were determined, and all the splice donor and acceptor sites conformed to the GT/AG rule. Approximately 1.2 kb of the 5'-flanking regions was sequenced, and putative regulatory elements were identified. These results will be useful for studies on the developmental and biological regulation of the TRKA gene and for further characterization of mutations in CIPA patients as well as elucidation of mechanisms responsible for rearrangement(s) observed in human tumors.
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PMID:Structure and organization of the human TRKA gene encoding a high affinity receptor for nerve growth factor. 929 Feb 60

The discovery of Rous sarcoma virus (RSV) led to the identification of cellular Src (c-Src), a non-receptor tyrosine kinase, which has since been implicated in the development of numerous human cancers. c-Src has been found to be highly activated in colon cancers, particularly in those metastatic to the liver. Studies of the mechanism of c-Src regulation have suggested that c-Src kinase activity is downregulated by phosphorylation of a critical carboxy-terminal tyrosine (Tyr 530 in human c-Src, equivalent to Tyr 527 in chicken Src) and have implied the existence of activating mutations in this C-terminal regulatory region. We report here the identification of a truncating mutation in SRC at codon 531 in 12% of cases of advanced human colon cancer tested and demonstrate that the mutation is activating, transforming, tumorigenic and promotes metastasis. These results provide, for the first time, genetic evidence that activating SRC mutations may have a role in the malignant progression of human colon cancer.
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PMID:Activating SRC mutation in a subset of advanced human colon cancers. 998 70

Tumour cell metastatic potential is significantly enhanced following treatment with HGF/SF, the ligand for the c-met receptor tyrosine kinase. Following c-met activation in tumour cells, phosphorylation of beta-catenin occurs, together with loss of intercellular adhesion and a gain in the motile and invasive nature of the cell. In this study we show that c-met is co-localised with beta-catenin and E-cadherin at regions of cell-cell contact in human colon cancer (HRT18 and HT115) and two breast cancer (MCF7 and MDA MB 231) cell lines. Immunoprecipitation studies demonstrated an association between c-met and members of the cadherin adhesion complex in these epithelial tumour cells, along with the membrane tyrosine protein phophatase, PTPmu. We conclude that the HGF/SF receptor, c-met, together with members of the cadherin/catenin cell-cell adhesion system and PTPmu, may form part of a protein complex in E-cadherin positive tumour cells that acts to regulate intercellular adhesion following HGF/SF stimulation.
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PMID:Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells. 1042 98

The non-receptor tyrosine kinase c-Src has been implicated in the development of numerous human cancers. c-Src is activated in colon cancers, particularly in highly metastatic cells, and its overexpression strongly correlates with tumor progression. C-terminal Src kinase (Csk) has been demonstrated to negatively regulate Src family tyrosine kinases through tyrosine phosphorylation at the C-terminal regulatory site (Tyr-527). We report herein that down-regulation of Src kinase activity by adenovirus-mediated csk gene transfer abrogated the highly metastatic phenotype of colon cancer cells. Overexpression of Csk decreased Src tyrosine kinase activity in NL-17 cells, the highly metastatic clone of mouse colon adenocarcinoma 26. Importantly, Csk overexpression in NL-17 cells resulted in significant suppression of in vivo metastasis, without affecting its tumorgenicity. Csk overexpression decreased the invasiveness of NL-17 cells through Matrigel, in vitro reconstituted basement membrane. Gelatin zymography confirmed the decreased protein levels of MMP-2 (gelatinase A) in the supernatants of Csk-overexpressed NL- 17 cells. These results provide a therapeutic basis for interfering with metastasis of colon cancer by csk gene-mediated down-regulation of Src kinase activity.
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PMID:Overexpression of the csk gene suppresses tumor metastasis in vivo. 1105 67

Human SRC encodes the non-receptor tyrosine kinase pp60(c-Src), which is activated in many human colon cancer cell lines (HCCLs) and tumors. We found that both c-Src protein and mRNA levels were elevated in a subset of HCCLs. Increased c-Src mRNA and protein levels correlated strongly with increased c-Src kinase activity. Nuclear run-on analysis and c-Src mRNA half-life determination demonstrated increased mRNA levels were due to increased transcription of the SRC gene. We also observed decreased c-Src mRNA stability in cell lines that displayed SRC transcriptional activation. Our findings provide the first evidence that SRC transcriptional activation is an important determinant of c-Src expression and activity in HCCLs.
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PMID:SRC transcriptional activation in a subset of human colon cancer cell lines. 1116 60

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


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