Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In order to search for clinically relevant cancer-associated genes and to define further the spectrum of immunogenic proteins, we applied SEREX (serological identification of antigens by recombinant expression cloning) to analyse genes expressed in colon adenocarcinoma. Eight different serum-reactive cDNA clones were isolated by immunoscreening from a colon cancer-derived cDNA expression library. mRNA expression studies showed that 2 of them, RHAMM and AD034, have a differential tissue distribution, and that 3 genes, NAP1L1, RHAMM and AD034, are overexpressed in tumours in comparison with the adjacent non-cancerous tissues. 5' RLM-RACE analysis of AD034, a sequence with a tyrosine kinase motif, revealed a frameshifting insertion of 32 bp, most likely generated by use of cryptic splice site in tumour-derived cDNA. Analysis of full-length RHAMM cDNA sequence revealed the presence of two splice variants, which are known to have a different sub-cellular localisation; expression of these splice variants is altered in colon cancer tissues. Serological responses to three antigens (C21ORF2, EPRS and NAP1L1) were found mainly in cancer patients' sera.
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PMID:Characterisation of tumour-associated antigens in colon cancer. 1238 9

Protein tyrosine kinase-7 (PTK7) is a receptor protein tyrosine kinase (RPTK)-like molecule that contains a catalytically inactive tyrosine kinase domain. We report here the genomic structure of the human PTK7 gene by screening a BAC library and DNA sequencing. The PTK7 gene is organized into 20 exons. All of the splicing junctions followed the conserved GT/AG rule. The exon-intron structure of the PTK7 gene in the region that encodes the catalytic domain was distinct from those of other RPTKs with strong homology. The 5'-flanking sequence of the PTK7 gene contains two GC boxes that concatenate Sp1 binding motifs, but does not contain either the TATA or CAAT consensus sequence. Using a luciferase reporter assay, it was demonstrated that the 883-bp 5'-flanking sequence is functional as a promoter of the PTK7 gene. We identified four new splicing variants in testis that could be derived from alternative splicing of exons 8-10, 10, a part of 12-13, and 16. The expression patterns of the splicing variants in the hepatoma and colon cancer cells were different from those of the testis. Our findings suggest that PTK7 is evolutionarily distinct from other RPTKs, and that the alternative splicing of PTK7 mRNA may contribute to its diverse function in cell signaling.
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PMID:Organization of the human PTK7 gene encoding a receptor protein tyrosine kinase-like molecule and alternative splicing of its mRNA. 1242 50

Between 1990 and 2001, altogether 28 new anticancer drugs were approved for use in Israel. The new agents include cytotoxic drugs, biologic compounds, and hormone therapies. Among the cytotoxic agents introduced, the taxanes, vinorelbine, gemcitabine, irinotecan, topotecan and temozolomide, represent important new drugs active in a range of solid malignancies including lung, breast, ovarian, bladder, pancreatic, and colon cancer as well as brain tumors. Epirubicin, idarubicin, and liposomal doxorubicin offer less toxic and in some instances more effective alternatives to older anthracylines for leukemia, breast cancer, ovarian cancer and other diseases. New oral agents are offering a chance for disease palliation without the need for burdensome intravenous access. Rituximab and trastuzumab have introduced monoclonal antibody therapy to the clinic, substantially improving the treatment of patients with lymphoma and breast cancer, respectively. The first tyrosine kinase inhibitor, a molecularly targeted therapy, imatinib, was approved for use in chronic myeloid leukemia and has also shown remarkable activity in gastrointestinal stromal tumors. A variety of aromatase inhibitors have provided less toxic and more effective hormone therapy for the treatment of breast cancer. The challenge for clinicians is to optimize the use of the new available agents for their patients' benefit, and the challenge for health policy-makers in Israel is to integrate the new anticancer pharmaceuticals into the basic health benefits package mandated for all citizens.
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PMID:New drugs for the treatment of cancer, 1990-2001. 1251 6

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

Beta-Catenin is a critical transducer of the Wnt signal pathway and plays an important role in many developmental and cellular processes. Deregulation of beta-catenin signaling has been observed in a broad range of human tumors. In this report, we investigated whether tyrosine kinase inhibitor STI-571 could inhibit the beta-catenin signaling activity and hence suppress cell proliferation. Our results demonstrated that STI-571 effectively inhibited the constitutive activity of beta-catenin signaling in human colon cancer cells as well as the Wnt1-induced activation of beta-catenin signaling in HOS, HTB-94, and HEK 293 cells. Furthermore, STI-571 was shown to effectively suppress the proliferation of human colon cancer cells. Finally, we demonstrated that the Wnt1-mediated activation of a GAL4-beta-catenin heterologous transcription system was effectively inhibited by STI-571. Thus, our findings suggest that tyrosine phosphorylation may play an important role in regulating beta-catenin signaling activity, and inhibition of this signaling pathway by STI-571 may be further explored as an important target for alternative/adjuvant treatments for a broader range of human cancer.
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PMID:Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity. 1270 73

Prostaglandin E(2) (PGE(2)) has been implicated as an inducer of angiogenesis in human colon cancer. Here, we demonstrate that PGE(2) exposure induces the expression of vascular endothelial growth factor (VEGF) mRNA in HCT116 human colon carcinoma cells that is mediated by the transcriptional activator hypoxia-inducible factor 1 (HIF-1). PGE(2) exposure induces the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT. Pharmacologic inhibition of ERK phosphorylation blocks the induction of VEGF mRNA and HIF-1alpha protein expression in response to PGE(2) stimulation. Inhibition of C-SRC tyrosine kinase activity also blocks PGE(2)-induced HIF-1alpha protein and VEGF mRNA expression without blocking ERK phosphorylation. In contrast, phosphorylation of AKT is dependent on ERK and C-SRC activity. Thus, the activity of multiple signal transduction pathways is required for the HIF-1-mediated induction of VEGF expression in colon cancer cells exposed to PGE(2).
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PMID:Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. 1272 58

Progression of human colon cancer is often associated with elevated expression and activity of the Src family tyrosine kinase (SFK). SFK is ordinarily in equilibrium between inactive and primed states by a balance of negative regulatory kinase Csk and its counteracting tyrosine phosphatase(s), both of which act on the regulatory C-terminal tyrosine of SFK. To evaluate the contribution of the regulatory system of SFK in cancer progression, we here modulated the equilibrium status of SFK by introducing wild-type or dominant-negative Csk in human epithelial colon cancer cells, HCT15 and HT29. Overexpression of wild-type Csk induced decreased SFK activation, increased cell-cell contacts mediated by E-cadherin, decreased the number of focal contacts and decreased cell adhesion/migration and in vitro invasiveness. Conversely, expression of a dominant-negative Csk resulted in elevated SFK activation, enhanced phosphorylation of FAK and paxilllin, enhanced cell scattering, an increased number of focal contacts, dramatic rearrangement of actin cytoskeleton and increased cell adhesion/migration and in vitro invasiveness. In these scattered cells, however, localization, expression and phosphorylation of either E-cadherin or beta-catenin were not significantly affected, suggesting that the E-cadherin-mediated cell-cell contact is indirectly regulated by SFK. Furthermore, all these events occurred absolutely dependent on integrin-mediated cell adhesion. These findings demonstrate that Csk defines the ability of integrin-SFK-mediated cell adhesion signaling that influences the metastatic potential of cancer cells.
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PMID:Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis. 1471 34

Little information is available as to the potential role of HER-2 as a therapeutic target in colon cancers, which express much fewer HER-2 receptors than breast cancer cells. Treatment of certain human colon cancer cell lines with the HER-2 inhibitory antibody mAb 4D5 demonstrated a role for HER-2 in mediating proliferation, apoptosis and tumorigenicity. However, only the cell lines that were dependent on autocrine EGFR-mediated cell proliferation were susceptible to the antiproliferative and antitumorigenic effects of HER-2 inhibition. The relative levels of HER-2, EGFR, HER-3 and HER-4 were not predictive of responsiveness to mAb 4D5. Treatment with HER-2 antibodies caused a decrease in HER-2 protein levels in all of the colon cancer cell lines and also significantly decreased EGFR levels but only in the EGFR-dependent cell lines. Treatment with mAb 4D5 caused the rapid ubiquitination and ligand-dependent downregulation of the EGFR in an EGFR-dependent colon cancer cell line. Treatment of athymic mice engrafted with EGFR-dependent colon cancer cells with mAb 4D5 caused tumor regression and a decrease in EGFR tyrosine phosphorylation in the tumor cells. EGFR-independent colon cancer cell xenografts were resistant to mAb 4D5 therapy. Combined inhibition of HER-2 and EGFR caused large areas of necrosis in EGFR-dependent colon cancer xenografts, suggesting a benefit of combined HER-2 and EGFR inhibitor therapy. Predicting clinical responsiveness of human colon cancer cells to anti-HER-2 and anti-EGFR therapy may require demonstration of EGFR tyrosine kinase dependency of the cells.
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PMID:Effects of trastuzumab on epidermal growth factor receptor-dependent and -independent human colon cancer cells. 1475 Jan 83

Dok-like adapter molecules represent an expanding family of pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domain-containing tyrosine kinase substrates with negative regulatory functions in hematopoietic cell signaling. In a search for nonhematopoietic counterparts to Dok molecules, we identified and characterized Dok-4, a recently cloned member of the family. dok-4 mRNA was strongly expressed in nonhematopoietic organs, particularly the intestine, kidney, and lung, whereas both mRNA and protein were expressed at high levels in cells of epithelial origin. In Caco-2 human colon cancer cells, endogenous Dok-4 underwent tyrosine phosphorylation in response to pervanadate stimulation. In transfected COS cells, Dok-4 was a substrate for the cytosolic tyrosine kinases Src and Fyn as well as for Jak2. Dok-4 could also be phosphorylated by the receptor tyrosine kinase Ret but not by platelet-derived growth factor receptor-beta or IGF-IR. In both mammalian cells and yeast, Dok-4 was constitutively localized at the membrane in a manner that required both its PH and PTB domains. The PH and PTB domains of Dok-4 were also required for tyrosine phosphorylation of Dok-4 by Fyn and Ret. Finally, wild type Dok-4 strongly inhibited activation of Elk-1 induced by either Ret or Fyn. The attenuation of this inhibitory effect by deletion of the PH domain and its restoration by the addition of a myristoylation signal suggested an important role for constitutive membrane localization of Dok-4. In summary, Dok-4 is a constitutively membrane-localized adapter molecule that may function as an inhibitor of tyrosine kinase signaling in epithelial cells.
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PMID:Pleckstrin homology and phosphotyrosine-binding domain-dependent membrane association and tyrosine phosphorylation of Dok-4, an inhibitory adapter molecule expressed in epithelial cells. 1496 42

Epidermal growth factor receptor (EGFR) is commonly overexpressed in a number of epithelial malignancies and is often associated with an aggressive phenotype [e.g., non-small cell lung cancer (NSCLC) and bladder cancer]. EGFR is present in over 50% of cases of NSCLC, head and neck squamous cell carcinomas (HNSCC) and colon cancer. Several EGFR-targeting agents have been recently developed (C225, ABX-EGF, E7.6.3, EMD 55900, ICR62, ZD1839, CP358774, PD168393, CGP75166/PKI166, CGP59326A, BIBX1382). The two most advanced EGFR inhibitors in development are C225 and ZD1839. C225 is an antibody directed against the ligand-binding domain of human EGFR, which competes for receptor binding with EGF and other ligands. In vitro, C225 inhibits EGFR tyrosine kinase activity and proliferation of EGFR-overexpressing squamous cell carcinoma cell lines. Synergy was observed with doxorubicin, cisplatin and radiation in preclinical models. In phase I trials, major toxicity has been dermatological (rash and acneic skin reactions); allergic reactions have also been observed in about 3% of cases. This agent, administered intravenously once weekly, is presently in phase III trials in HNSCC and colon cancer. ZD1839, a synthetic molecule which targets the EGFR ATP binding site, is a very specific inhibitor of EGFR tyrosine kinase activity. Synergy has been observed with paclitaxel and cisplatin. In phase I trials, responses were seen in advanced NSCLC, and cutaneous toxicity and diarrhea were the most important side effects. Oral chronic daily administration is feasible. Two large randomized trials have been completed in advanced NSCLC in combination with chemotherapy. A large phase II study in second and third line has demonstrated a single agent activity of 18.5%. Another large phase II study in patients who received prior platinum and docetaxel obtained a response rate of 11%. There was no difference in response rate between the 250 and the 500 mg/day doses, but side effects were higher in patients who received the 500 mg dose. A very similar small molecule, OSI-774, has also shown activity in this setting. Two large randomized phase III studies of ZD1839 have recently been completed and analyzed in which two doses of ZD1839 (250 or 500 mg/day) or placebo were given in combination with two different chemotherapy regimens (carboplatin-paclitaxel or carboplatin-gemcitabine). These studies failed to demonstrate an increase in survival by adding ZD1839 together with chemotherapy in patients with advanced NSCLC.
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PMID:The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. 1498 46


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