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)

The serum-free medium conditioned by the human colon cancer cell line HT-29 contains insulin-like growth factors (IGF) that are entirely complexed to binding proteins (IGF-BP). Gel filtration in acid conditions of the cell-conditioned medium permits separation of IGF-BP from two molecular forms of IGF of 15,000 and 7,500 Mr. As determined by ligand blotting, IGF-BP are heterogeneous and constituted of three molecular forms of 31,000, 28,000, and 26,000 Mr. Using IGF-I and IGF-II radioreceptor assays, IGF-I radioimmunoassay (RIA), and competitive protein-binding assay specific for IGF-II, it is shown that the IGF-type eluting in 15 K and 7.5 K position from gel filtration is restricted to IGF-II. Its concentration is approximately 6 ng/10(6) HT-29 cells with 60% present as a high-molecular-weight form of IGF-II. This large 15 K IGF molecule is devoided of any IGF-binding activity and might represent incomplete processing of pro-IGF-II peptide. By contrast, the level of IGF-I detected by RIA is barely measurable and considered negligible (0.57 pg/10(6) HT-29 cells). Although these IGF-II-like peptides exhibit a growth-promoting activity on FR3T3 fibroblasts, they cannot stimulate, as recombinant IGF-I or IGF-II, 3H-thymidine incorporation into DNA of HT-29 cells, whatever the experimental conditions used. Finally, we have shown that IGF binding is restricted predominantly to the basolateral domain of the cell membrane by using HT-29-D4 clonal cells, derived from the parental HT-29 cell line, maintained in a differentiated state by culture in a medium in which glucose is replaced by galactose.
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PMID:Production of insulin-like growth factor II (IGF-II) and different forms of IGF-binding proteins by HT-29 human colon carcinoma cell line. 169 80

We have purified a protein from serum-free conditioned medium of the HT29 human colon adenocarcinoma cell line based on its ability to inhibit the proliferation of the same cell line. The purification procedure consisted of acid gel permeation, semipreparative, and analytical reversed-phase chromatographies. The high-pressure liquid chromatography-purified colon cancer cell growth inhibitor migrates as a single band of 27 and 34 kDa on sodium dodecyl sulfate/polyacrylamide gels under nonreducing and reducing conditions, respectively. NH2-terminal amino acid sequence analysis of the first 32 residues has demonstrated that this protein belongs to the insulin-like growth factor-binding protein (IGFBP) family. More precisely, this growth inhibitor appeared to be identical to the recently cloned human IGFBP-4. This IGFBP (HT29-IGFBP) has been characterized by performing ligand blotting and competitive binding experiments. The affinity of HT29-IGFBP for insulin-like growth factor (IGF) II (approximately 3.4 x 10(10) M-1) is slightly greater than its affinity for IGF-I (approximately 1.4 x 10(10) M-1). HT29 cells also produce two other isoforms (28 and 31 kDa, nonreduced) of the HT29-IGFBP having the same partial NH2-terminal amino acid sequence as the 27-kDa protein. The monoclonal antibody alpha IR-3 is known to block the mitogenic actions of IGFs. alpha IR-3 inhibited the growth of HT29 cells, thus suggesting that IGFs are required for the growth of these colon cancer cells.
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PMID:Purification of a colon cancer cell growth inhibitor and its identification as an insulin-like growth factor binding protein. 170 85

The HT-29 human colon cancer cell line has previously been shown to secrete high amounts of insulin-like growth factor II (IGF-II). The recent demonstration that soluble IGF-II/mannose 6-phosphate receptor was present in fetal serum prompted us to search for a release of type-II IGF receptor by these human colonic carcinoma cells. Serum-free conditioned medium from the HT-29 cell line was gel filtered on Sephadex G-200. There was significant binding of [125I]IGF-II to the void volume fractions in addition to binding to the 40-kDa IGF-binding protein (IGF-BP) fractions. Competitive binding studies using [125I]IGF-II and the void volume pool showed a pattern typical of the type-II receptor. It exhibited a high affinity for IGF-II (KD = 0.4 nM), but had a low affinity for IGF-I (KD = 6.8 nM), and no detectable affinity for insulin. Additional evidence was provided by affinity cross-linking of [125I]IGF-II to the same high-molecular-weight material which demonstrated a major specific band at 250 kDa after reduction of disulfide bonds. In contrast, the type-I IGF receptor was undetectable. The extracellular type-II IGF receptor was not a significant carrier for IGF-II since virtually all IGF-II secreted by HT-29 cells was associated with IGF-BP. The presence of a soluble IGF-II/mannose 6-phosphate receptor in the culture medium from colonic cancer cells suggests that it may play an important role in tumor pathogenesis.
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PMID:Type-II insulin-like growth-factor receptor in conditioned medium from HT-29 human colon carcinoma cell line. 184 38

We previously reported that even though virtually all human colon cancers were positive for IGF-I receptors, only 50% responded to growth effects of insulin-like growth factor (IGF)-I (1-100 nM). The present studies were undertaken to determine whether expression and secretion of IGFs (IGF-I, IGF-II) and IGF-binding proteins (BPs; 1-6) were perhaps different in IGF-responsive (COLO 205, COLO 320, Caco-2) and IGF-nonresponsive (HCT 116, HT-29, DLD-1) cells. Several bands (2.0-6.0 kb) of IGF-II mRNA transcripts were detected in all the cell lines; none expressed IGF-I. Significant concentrations of IGF-II (0.2-0.9 ng/10(6) cells) were measured in the conditioned media (CM) of the cells. All cell lines expressed BP2 and/or BP4 mRNA and secreted BP4 (24 kDa) and/or BP2 (32.5 kDa); BP1 was not detected in any cell line. Interestingly, BP3 mRNA was measured only in the responsive cell lines. The relative concentration of total BPs tended to be higher in the CM of nonresponsive cells. Interestingly, a large concentration of 44- to 48-kDa BP (BP3?) was associated with the membranes of only the responsive cell lines. Our present studies thus demonstrate that human colon cancers do not secrete IGF-I and BP1. Of all the IGF-related factors examined, the quantity and the type of BPs expressed by the human colon cancer cell lines (especially BP2, BP4, and BP3) may significantly dictate the growth response of the cells to exogenous IGF-I.
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PMID:Expression of IGF-II and IGF-binding proteins by colon cancer cells in relation to growth response to IGFs. 752 48

Ezrin is a membrane-cytoskeleton linker protein and belongs to the TERM family. It has been implicated in the membrane ruffling, motility, and metastatic process of tumour cells. This study examined the effects of a range of cytokines on the expression of ezrin in the human colon cancer cell line, HT29. Levels of ezrin were determined by Northern and Western blotting and indirect immunofluorescence. We report that IL-2, IL-8, IL-10 and IGF-I had an inhibitory effect on the expression, whereas EGF and IL-11 enhanced cellular ezrin levels. Immunofluorescence confirmed that these changes were seen both in cytosol and generalised membrane. It is concluded that ezrin expression in tumour cells can be regulated by cytokines and this bears importance in the understanding of its role in tumour biology.
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PMID:Cytokine regulation of ezrin expression in the human colon cancer cell line HT29. 868 42

We have compared the expression of insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in ten paired samples of normal and tumour colonic tissue with regard to both mRNA and protein. We have compared sensitivity of these tissues to IGF-I using primary cultures of epithelial cells of colonic mucosa, and we have examined the production of IGFs and IGFBPs by these cells. In the tissues, IGFBP-2 mRNA was expressed in all normal and cancer samples but other IGFBPs showed variable expression. mRNAs for IGF-I were expressed in all normal and cancer tissues but IGF-II mRNA was only detected in cancer tissue (3 out of 10). Immunostaining of sections of normal and cancer tissue was negative for IGF-I and IGF-II; IGFBP-2 was positive in 2 out of 10 cancer tissues and 7 out of 10 normal tissues; IGFBP-3 was positive in 7 out of 10 cancer tissues and 7 out of 10 normal tissues; and IGFBP-4 was positive in 5 out of 10 cancer tissues and 6 out of 10 normal tissues. In the cells in culture, cancer cells showed increased incorporation of [35S]methionine into protein and [3H]thymidine into DNA (P < 0.02) when treated with IGF-I. Western blotting of serum-free conditioned media from cells in culture showed that 8 out of 10 normal and 3 out of 10 cancer cultures produced a 32-kDa immunoreactive IGFBP-2. No IGFBP-3 was secreted by any culture but 24-kDa IGFBP-4 was found in 3 out of 10 normal and 5 out of 10 cancer tissues. Because of the discrepancy between mRNA and protein expression for IGFBP-2, degradation of native IGFBPs was assessed using tissue extracts. Colon cancer extracts were able to degrade exogenous IGFBP-2, IGFBP-3 and IGFBP-4, whereas normal tissue extracts were without effect on IGFBP-2. We conclude that IGFBPs are synthesized and secreted by cells of the colonic mucosa but that proteolysis of secreted IGFBP-2 occurs in colon cancer tissue. This selective degradation may confer a growth advantage.
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PMID:Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers. 921 34

Human colon cancer cell lines COLO205, HT29 and SW620 are known to secrete insulin-like growth factor II (IGF-II) and its modulatory binding proteins (IGFBPs). We have characterised the sensitivity of these cell lines to exogenous IGF-I and have examined the effects of their autocrine IGFBPs on these responses. Cells cultured in serum-free medium were treated with 1-100 ng/ml IGF-I, or des(1,3)IGF-I, a truncated IGF-I with low affinity for IGFBPs. DNA synthesis was determined by 24 h incorporation of 3H-thymidine. Experiments were repeated in the presence of 24 h cell-conditioned media containing endogenous IGFBPs. In all 3 cell lines, cell-conditioned media reduced sensitivity to IGF-I but not to des(1,3)IGF-I suggesting that IGFBPs in the cell-conditioned media of colon cells inhibit IGF-I action. IGFBPs in the cell layer and 24 h cell-conditioned media were identified by Western ligand and antibody analyses. IGFBP-4 was secreted by all cell lines and IGFBP-2 from the COLO205 and SW620 cells lines but not the HT29 cells. No IGFBP-3 was secreted by any of the cell lines but IGFBP-3 was found in the cell layer in all of the cell lines. When endogenous secreted IGFBPs were removed, cell lines were consistently more sensitive to IGF-I than des(1,3)IGF-I suggesting that IGFBP-3 associated with the cell layer enhances responses to IGF-I. This is in contrast to the effects of the secreted IGFBPs. Differential modulating actions of IGFBPs may be important in regulating colon cell turnover.
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PMID:Insulin-like growth factor binding proteins as mediators of IGF-I effects on colon cancer cell proliferation. 938 91

Epidemiologic data and animal models have demonstrated a correlation between dietary fat composition and colon cancer risk. We have previously found that dietary fat alters cell proliferation in rat colon, which may influence the risk of colon cancer. Growth factors, including insulin-like growth factor (IGF) I and II, regulate the cell cycle in most mammalian tissues. Hence, we measured IGF-I and IGF-II receptor expression in colonocytes from Sprague-Dawley rats fed diets containing either beef tallow (BT) or corn oil (CO) at 12, 30 or 37% of energy for 4 wk. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using an internal standard was used to examine the relative expression of both IGF-I and II receptor mRNA in three sections of the colon. The IGF-I receptor protein was also measured by Western immunoblot. In the distal colon, IGF-I receptor gene expression and protein increased significantly as the percentage of CO increased. In both proximal and middle colon, an increased percentage of BT resulted in significantly increased IGF-II receptor expression. In the proximal colon, IGF-II receptor expression decreased with increasing CO concentration, whereas in the middle colon, rats fed 37% CO had significantly higher IGF-II receptor expression than rats fed 12 or 30% CO. IGF-II receptor gene expression in proximal colon decreased with increased fat quantity, independently of fat source, whereas in the middle colon, increased fat quantity resulted in increased IGF-II receptor expression. Thus IGF-I and IGF-II receptor mRNA and IGF-I receptor protein level in colon mucosa were significantly altered by dietary fat source and quantity, thereby suggesting a potential influence of dietary fat on the endocrine regulation of colon cell mitogenesis.
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PMID:Insulin-like growth factor-I and II receptor expression in rat colon mucosa are affected by dietary lipid intake. 944 37

We investigated the role of insulin-like growth factor (IGF)-I and IGF-binding proteins (IGFBPs) in the regulation of vascular endothelial growth factor (VEGF) expression in colon cancer cells and the mechanism by which this regulation occurs. HT29 human colon cancer cells were treated with IGF-I for various time periods. VEGF mRNA expression increased within 2 h and peaked at 24 h. SW620 colon cancer cells exhibited a peak induction of VEGF mRNA 8 h after IGF-I treatment. IGF-I induction of VEGF was confirmed at the protein level. In experiments using transient transfection of VEGF promoter-reporter constructs into HT29 cells, IGF-I increased the activity of the VEGF promoter, and pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA by IGF-I. The half-life of VEGF mRNA was not prolonged by treatment with IGF-I. Blocking the activity of IGFBP-4 did not significantly modulate the effect of IGF-I induction of VEGF mRNA in HT29 cells. Treating cells with des-(1-3)-IGF-I (an active derivative of IGF-I that does not bind to binding proteins) had effects on VEGF mRNA expression that were similar to those of IGF-I. These findings suggest that IGF-I regulates VEGF expression in human colon cancer cells by induction of transcription of the VEGF gene. IGFBPs do not significantly affect IGF-I induction of VEGF.
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PMID:Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. 973 15

Perturbations of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases such as prostate specific antigen (PSA), and cathepsin D have been identified in prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have been found to be negatively correlated to the risk of cancer. Interestingly, IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an IGF-independent mechanism. Recent case-control studies have found an approximately 10% increase in the serum levels of IGF-I in patients with prostate, breast and lung cancers, which are among the most frequently diagnosed cancers. While the studies indicate an association between serum IGF-I levels and cancer risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for autocrine tissue IGF-I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in serum. However, the role of GH in controlling prostate, breast and lung growth and carcinogenesis remains unclear from animal studies. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with prostate, breast or lung cancers, although colon cancer mortality may be increased. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of cancer, interpreting the risk associated with therapies such as GH replacement must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their cancer risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH recipients should become standard of care.
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PMID:IGFs and human cancer: implications regarding the risk of growth hormone therapy. 1059 43


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