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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biologically realistic mechanistic models of carcinogenesis by TCDD are composed of equations representing biochemical events leading to altered expression of proteins involved in the response or equations representing the kinetics of proliferation of clones of mutant cells. A biochemically augmented physiological dosimetry model reproduces the observed altered expression of liver proteins in female rats exposed to dioxin. The model suggests that oxidation of estradiol to DNA reactive quinones or semiquinones by CYP1A2 protein induced by TCDD may contribute to an increased mutational rate. It suggests that TCDD-stimulated production of a peptide ligand of the epidermal growth factor (EGF) receptor and subsequent activation of the receptor's tyrosine kinase activity may increase the rate of proliferation of susceptible cells. These calculated quantities can serve as indices of toxicity and can be used to predict tumor incidence as a function of exposure.
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PMID:Biochemical mechanisms and cancer risk assessment models for dioxin. 748 48

The protooncogene c-kit encodes a transmembrane receptor-type tyrosine kinase which belongs to the beta-PDGER/CSF-1 receptor tyrosine kinase family. The interaction between c-kit receptor and its corresponding ligand, stem cell factor (SCF), has been suggested to be involved in embryogenesis as well as carcinogenesis via the autocrine/paracrine system. In the present study, cancer cell lines and normal/benign/malignant tissues of the human female genital tract were examined for the expression of both c-kit and SCF by Northern blot and immunohistochemical analyses. Two of 16 cell lines showed mRNA expression of both c-kit and SCF, while 2 and 12 cell lines expressed c-kit and SCF, respectively. In tissues, several cases of malignant tumors, including three cervical cancers, one ovarian cancer, and one ovarian immature teratoma, expressed mRNA of both c-kit and SCF. In normal tissues, squamous epithelium expressed SCF immunohistochemically, while c-kit protein was detected only in melanocytes. Some tissues of malignant tumors, one squamous cell carcinoma of the cervix, two small cell carcinomas of the cervix, two serous adenocarcinomas of the ovary, and two immature teratomas of the ovary, expressed both c-kit and SCF proteins immunohistochemically. It is also notable that c-kit protein was expressed only in malignant germ cells of dysgerminomas, while SCF was expressed in the connective tissues surrounding germ cells. The present study suggests that the c-kit/SCF system may play an important role in the carcinogenesis of the female genital tract.
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PMID:Coexpression of the c-kit receptor and the stem cell factor in gynecological tumors. 751 96

C-CAMs are epithelial cell-adhesion molecules of the immunoglobulin supergene family with sequences highly homologous to carcinoembryonic antigen (CEA). C-CAMs and their human homologues, biliary glycoproteins, are unique among the CEA-family proteins in that they have cytoplasmic domains. Furthermore, alternative splicing generates C-CAM isoforms with different cytoplasmic domains, suggesting that the cytoplasmic domains of C-CAM may play important roles in regulating the function or functions of C-CAM. By using both sense and antisense approaches, we have shown that C-CAM1 is a tumour suppressor in prostate carcinogenesis. This observation raises the possibility that the cytoplasmic domain of C-CAM1 may be involved in signal transduction or interaction with cytoskeletal elements to elicit the tumour suppressor function. The cytoplasmic domain of C-CAM1 contains several potential phosphorylation sites, including putative consensus sequences for cyclic AMP-dependent kinase and tyrosine kinase. One of the potential tyrosine phosphorylation sites is located within the antigen-receptor homology (ARH) domain. The ARH domain of the membrane-bound IgM molecule is necessary for signal transduction in B-cells. These structural features suggest that the cytoplasmic domain of C-CAM1 may be important for signal transduction. To test this possibility, we generated several site-directed C-CAM1 mutants and tested their ability to support adhesion and their abilities to be phosphorylated in vivo. Results from these studies revealed that Tyr-488 is phosphorylated in vivo. However, replacing this tyrosine with phenylalanine did not significantly compromise its adhesion function. Similarly, Ser and Thr residues are phosphorylated in vivo, but deletion of the potential cyclic AMP-dependent kinase site did not significantly reduce the adhesion function. These results suggest that the kinase phosphorylation sites in the cytoplasmic domain of C-CAM1 are not required for the adhesion function. However, these phosphorylation sites are probably involved in the regulation of C-CAM-mediated signal transduction. Thus, there are probably distinct structural requirements for the adhesion and the signal transduction functions of C-CAM. Incidentally, a C-CAM1 deletion mutant containing a 10-amino-acid cytoplasmic domain was able to support adhesion activity. This is in contrast to our previous finding that a C-CAM isoform, C-CAM3, with a 6-amino-acid cytoplasmic domain could not support cell adhesion. This result indicates that the extra four amino acids, which are absent in C-CAM3 and contain a potential Ser/Thr phosphorylation site, are important for the adhesion function.
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PMID:Structure and function of C-CAM1: effects of the cytoplasmic domain on cell aggregation. 757 60

For identification of the protein-tyrosine kinases that are expressed in embryo stomach and gastric cancer, a 16-day rat embryo stomach and two human gastric cancer cDNA expression libraries were screened with an anti-phosphotyrosine antibody. Eight cDNAs encoding protein-tyrosine kinase were isolated, and Northern blot analysis revealed that five out of eight clones were highly expressed in rat embryo stomach, but not in adult rat stomach. From nucleotide sequence analysis, these five cDNAs were identified as elk, erk, esk, TTK and fyn, respectively. We report here that the expression levels of two families of receptor type tyrosine kinase genes, elk/erk and esk/TTK are developmentally regulated in rat stomach and highly expressed in human gastric cancer tissues. These findings suggest that elk/erk and esk/TTK genes play important roles in embryonic development and carcinogenesis of the stomach.
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PMID:Identification of protein-tyrosine kinase genes preferentially expressed in embryo stomach and gastric cancer. 768 22

In the present work we have investigated activation of phosphorylation of plasma membrane insulin-like growth factor-I receptors (IGF-IR) by diethylstilbestrol (DES). Insulin-like growth factor-I (IGF-I) stimulated the activity of membrane protein tyrosine kinase(s) (PTK) in both normal and DES-treated hamster kidneys. The level of IGF-I-stimulated PTK(s) almost doubled after 15 days of DES treatment. Autophosphorylation experiments revealed that phosphorylation of a 95 kDa band (presumably the beta subunit of IGF-IR) was 2-fold higher in the membranes of kidney from DES-treated animals compared with controls. To understand the mechanism of activation of IGF-I-dependent PTK by DES, we investigated the relationship between the binding capacity of IGF-I to membrane proteins and the level of IGF-IR. The binding of [125I]IGF-I to membranes from the DES-treated group was 30% higher than that of age-matched normal kidney (P < 0.001). Scatchard analysis of the binding data for both normal and DES-treated hamster kidney revealed a single class binding site for IGF-I with a dissociation constant (Kd) of 4.1 and 4.6 nM and a maximum binding capacity (Bmax) of 1786 and 2086 fmol/200 micrograms protein respectively. Therefore, the difference observed in [125I]IGF-I binding between DES-treated and normal kidney membranes may be partially due to an increase in the number of IGF-I binding sites, with no change in the affinity of the receptors for IGF-I. An enhanced level of IGF-IRs in membranes from DES-treated animals was visualized by autoradiography following affinity labeling of membrane proteins subjected to SDS-PAGE. Under reducing conditions a molecular band of 132 kDa was evident. The 132 kDa band represents the alpha-subunit of IGF-IRs. Northern blot analyses revealed that DES treatment increased the level of IGF-IR mRNA 2-fold compared with that of controls. These findings suggest that an enhanced level of IGF-IR coupled with qualitative changes may be responsible for the activation of IGF-I-dependent PTK on DES exposure. Whether the stimulation of IGF-IR phosphorylation by exposure to a carcinogenic dose of DES may be a factor in the induction of renal cancer in Syrian hamsters is not clear.
Carcinogenesis 1995 Jun
PMID:Activation of phosphorylation of plasma membrane insulin-like growth factor-I receptors in the kidney of Syrian hamsters by diethylstilbestrol. 778 52

Ninety potential chemopreventive agents were screened using 6 chemoprevention-associated biochemical end points. These compounds were tested using rodent (tracheal epithelial or liver) cells and human cells [neonatal foreskin fibroblasts, bronchial epithelial cells, or human leukemic cells (HL-60)]. The effects measured were: (a) inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tyrosine kinase activity in HL-60 cells; (b) inhibition of TPA-induced ornithine decarboxylase (ODC) activity in rat tracheal epithelial cells; (c) inhibition of poly(ADP-ribose)polymerase in propane sultone-treated primary human fibroblasts; (d) inhibition of benzo[a]pyrene(B[a]P)-DNA binding in human bronchial epithelial cells; (e) induction of reduced glutathione in Buffalo rat liver cells; and (f) inhibition of TPA-induced free radical formation in primary human fibroblasts or HL-60 cells. Fifty compounds were highly effective in inhibiting TPA-induced tyrosine kinase activity. This assay identified compounds from a wide variety of chemical classes as effective inhibitors, including all the vitamins, retinoic acid analogues, protein kinase C inhibitors, and chemicals belonging to the amino acid category. Fifty-two chemicals were classified as highly positive compounds when examined for their ability to inhibit TPA-induced ODC activity. These agents showed a dose-dependent inhibition or inhibition at all doses. Retinoids, in general, exhibited strong inhibition of ODC activity. A category of compounds showing dose-dependent inhibition were the sulfur compounds, especially the thiols and thiones. Among the natural products, terpenes were strong inhibitors of ODC. Forty-seven compounds were classified as strong inhibitors of poly(ADP-ribose)polymerase. In the carcinogen-DNA binding inhibition assay, 21 compounds were identified as strong inhibitors, which include phenolic compounds as well as sulfur compounds. Vitamins and their analogues were also good inhibitors. Testing for induced glutathione yielded 19 compounds that were good inducers. Sulfur-containing compounds and most of the phenolic compounds were also inducers of glutathione. Twenty compounds were highly positive for inhibition of TPA-induced free radical formation. A significant number of phenolic and sulfur compounds were again strong oxygen radical scavengers. Some antiinflammatory agents were also identified as free radical inhibitors. In general, retinoids were quite active in all the assays. Eight compounds were positive in all of the six assays; these were vitamin C (ascorbic acid), bismuththiol, esculetin, etoperidone, folic acid, hydrocortisone, indole-3-carbinol, and tocopherol succinate. Agents that were positive in these assays may inhibit the carcinogenesis process by similar mechanisms in humans and are identified as candidates for development as chemopreventive agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Screening of potential chemopreventive agents using biochemical markers of carcinogenesis. 795 13

Tyrosine phosphorylation is widely recognized as playing important roles in cell differentiation, proliferation, and carcinogenesis. We have used the polymerase chain reaction (PCR) method to identify protein tyrosine kinases that are expressed in the skin. Mixed oligonucleotide probes were used to amplify and screen a neonatal murine skin cDNA pool for clones encoding amino acid contiguities whose conservation is characteristic of the protein tyrosine kinase family. When the PCR products were sequenced, 13 distinct clones were found, of which one is novel to date and has provisionally been named tks (for tyrosine kinase identified from skin). Sequence homology comparison showed that the tks gene is homologous to the src and fes/fps families. Northern blotting using PCR products of tks as a probe revealed that the mRNA of tks is detected ubiquitously and weakly in other tissues such as brain, lung, liver, thymus and kidney. This fact suggests that the tks gene is expressed in widely distributed cell types.
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PMID:Identification of a novel cDNA clone encoding protein tyrosine kinase in murine skin. 796 51

Membrane receptors have appeared early in evolution as the means for the unicellular organism to sense its environment. With the emergence of social cellular life in multicellular organisms, membrane receptors have acquired the additional functions of sensing the presence of similar cells (as in the aggregation phenomenon of Dictyostelium discoideum) (Klein et al., 1988) or the presence of the mate (Saccharomyces cerevisiae) (Cross et al., 1988), and to detect endocrine signals emitted by cells in distant tissues. As the latter function is central to homeostasis and regulation of cell growth, the downstream regulatory cascades under receptor control are the subject of intense research with implications in virtually all fields of biomedical science. The impact of the analysis of tyrosine kinase-activated cascades on our understanding of carcinogenesis is but one example of such an advance.
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PMID:Constitutively active receptors as a disease-causing mechanism. 805 51

The ability of platelet activating factor (PAF), a potent endogenous inflammatory agent, to induce phenotypic transformation of primary rat embryo cells (RECs) was investigated. RECs are composed predominantly of fibroblasts, with some epithelial cells and a few neuronal and muscle cells. A 1 h period of treatment with PAF (1 x 10(-8)-1 x 10(-6) M) increased the ability of RECs to (i) form foci, (ii) reach a high saturation density in complete medium, (iii) grow in low serum-containing medium and (iv) exhibit anchorage-independent (AI) growth. Similar changes were achieved with C-PAF (1 x 10(-10)-1 x 10(-8) M), an active, non-metabolizable analog of PAF, but not by lyso-PAF (1 x 10(-10)-1 x 10(-6) M), a biologically inactive metabolite of PAF. All of the PAF-induced phenotypic changes could be inhibited by pretreatment with a PAF receptor antagonist, CV3988 (1 x 10(-6) M). Pretreatment of RECs with genestein (1 microgram/ml) also completely inhibited all four measures of PAF-induced REC transformation indicating that tyrosine kinase activity may be required for the observed changes in phenotype. Pretreatment with indomethacin (2 x 10(-7) M) blocked the PAF-induced increases in focus formation and saturation density without affecting PAF-induced alterations in growth in low serum or AI growth. This indicates that PAF may exert some of its effects through a cyclooxygenase product. Pretreatment with staurosporine (5 x 10(-8) M) failed to alter any of the PAF-induced effects, suggesting that protein kinase C activity is not involved in REC transformation by PAF. Our results provide the first evidence that PAF, released by activated phagocytes in and around areas of inflammation, may contribute to the process of malignant transformation.
Carcinogenesis 1993 Jul
PMID:Platelet activating factor, an endogenous mediator of inflammation, induces phenotypic transformation of rat embryo cells. 839 43

The c-erbB-2 proto-oncogene (HER-2/neu) codes for a transmembrane, tyrosine kinase, 185 kD oncoprotein (p185erbB2), which is related to the epidermal growth factor receptor. p185erbB2 overexpression occurs in carcinomas at many sites, including the uterine cervix, and predicts poor clinical outcome. The authors hypothesize that p185erbB2 immunohistochemistry will provide additional information in the evaluation of uterine cervix carcinomas with glandular differentiation (CCGD), a difficult and more frequent clinical problem. Paraffin sections from 82 CCGDs including 41 pure adenocarcinomas and 41 adenosquamous carcinomas (7 glassy cell predominant and 34 exhibiting a gland forming component) are immunostained with anti-p185erbB2 (CB11 monoclonal, Novacastra Laboratories, Newcastle upon Tyne, UK). Seventy-seven percent of CCGDs exhibit p185erbB2 immunoreactivity with distinct plasma membrane localization (M) in 50%, the remaining 27% show cytoplasmic staining only. Adjacent benign tissue is negative. The p185erbB2 staining intensity and distribution is as follows: 54.9% strong diffuse (SD, > or = 50% cells positive) with 40.2% M, 17.1% strong focal (SF, < 50% cells positive) with 9.8% M, and 4.9% weak with no M. Immunoreactivity occurs in both squamous and glandular areas of adenosquamous carcinomas. Endometrioid histology is associated with absence of p185erbB2 (P < .01); all other histopathologic features show no association. Follow-up information is available in 77 patients: 37 exhibit recurrent disease (8 pelvic, 15 distant and 14 both) at 1 to 144 months (mean 34, median 16) and 40 were disease free at 12 to 216 months (mean 75, median 64). Strong p185erbB2 immunoreactivity predicts recurrence at 24 months (P < .05) but not overall recurrence at longer follow-up periods. Recurrent disease is associated with nuclear grade (P < .00001); high clinical stage (P < .001); vascular space invasion (P < .001); large size on clinical exam or pathologic evaluation (P < .005); and pelvic lymph node involvement (P < .05). Considering only patients in good prognosis groups, p185erbB2 immunoreactivity does not predict recurrence. Strong p185erbB2 immunoreactivity is associated with stage 3,4 disease (P < .01). p185erbB2 expression is associated with CCGD carcinogenesis but occurs late in the disease, in patients who present at late stage, hindering its prognostic predictive value. p185erbB2 immunolocalization may have a diagnostic role in confirming CCGD in histologically challenging cases, predicting high stage at initial biopsy, and defining therapeutic strategies.
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PMID:c-erbB-2 oncoprotein overexpression in uterine cervix carcinoma with glandular differentiation. A frequent event but not an independent prognostic marker because it occurs late in the disease. 885 48


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