Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-8 serves as a major chemoattractant for neutrophils and has also been proposed to affect cancer progression. In the present study, we show that IGF-I stimulates IL-8 mRNA expression and IL-8 secretion in the leukemic cell line HL-60. Stimulation of IL-8 expression was completely attenuated by two inhibitors of mitogen-activated protein kinase (MAPK) kinase (MEK), which phosphorylates the MAPKs extracellular-regulated kinase (ERK)1 and ERK2, and by the c-Jun NH2-terminal kinase (JNK) inhibitor SP600125. In contrast, inhibitors of p38 MAPK and phosphatidylinositol-3 kinase (PI3K) did not abrogate the effect of IGF-I. We also show that IGF-I stimulates the activation of ERK1 and ERK2, but we could not detect any effect of IGF-I on the phosphorylation of p38, JNK(p46) or JNK(p54). Collectively, our results suggest that basal JNK activity and activation of the MEK-ERK pathway are required for upregulation of IL-8 by IGF-I in HL-60 cells.
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PMID:IGF-I stimulates IL-8 production in the promyelocytic cell line HL-60 through activation of extracellular signal-regulated protein kinase. 1457 64

Multiple large case-control studies in the past five years have reported positive associations between high circulating levels of the insulin-like growth factor (IGF)-I and risk for different types of cancer. Correlations certainly do not prove causation, but the reproducibility of this finding implies this is a hypothesis worth further examination through more mechanistic studies. IGF-I binds to the IGF-I receptor, a tyrosine kinase receptor that transduces signals to the nucleus and mitochondrion primarily via the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways. Examples will be provided to illustrate how IGF-I signaling may contribute to each stage of cancer progression: malignant transformation, tumor growth, local invasion and distant metastases, and resistance to treatment. In addition to direct contributions to each of these stages, IGF-I may promote cancer indirectly, through interactions with oncogenes and tumor suppressors, interactions with other hormones (especially the sex steroids in breast and prostate cancers) and interactions with the IGF binding proteins (IGFBPs). Finally, circulating IGF-I may facilitate cancer development though it likely does not cause cancer to form. Prompted by the accumulating evidence, investigations are also being pursued to modulate the IGF system as a possible means of cancer prevention or treatment.
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PMID:Mechanisms by which IGF-I may promote cancer. 1468 66

Growth hormone releasing hormone (GHRH) is known to have multiple anabolic effects and immune-stimulatory effects. Previous studies suggest that treatment with anabolic hormones also has the potential to mitigate the deleterious effects of cancer cachexia in animals. We studied the effects of plasmid-mediated GHRH supplementation on tumor growth and the role of antitumor immune cells with two different human tumor cell lines, NCI-H358 human bronchioalveolar carcinoma and MDA-MB-468 human breast adenocarcinoma, subcutaneously implanted in nude mice. GHRH supplementation by delivery of human GHRH from a muscle-specific GHRH expression plasmid did not increase tumor progression in tumor-bearing nude mice. Male animals implanted with the NCI-H358 tumor cell line and treated with the GHRH-expressing plasmid exhibited a 40% decrease in the size of the tumors (P<.02), a 48% increase in white blood cells (P<.025) and a 300% increase in monocyte count (P<.0001), as well as an increase in the frequency of activated CD3+ and CD4+ cells in the tumors, compared to tumors of control animals. No adverse effects were observed in animals that received the GHRH-plasmid treatment. The present study shows that physiological stimulation of the GHRH-GH-IGF-I axis in mice with cancer does not promote tumor growth and may provide a viable treatment for cancer cachexia in humans.
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PMID:Growth hormone releasing hormone plasmid supplementation, a potential treatment for cancer cachexia, does not increase tumor growth in nude mice. 1537 78

We earlier demonstrated that oral infusion of green tea polyphenols inhibits development and progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Evidence indicates that elevated levels of IGF-I with concomitant lowering of IGF binding protein (IGFBP)-3 are associated with increased risk for prostate cancer development and progression. In this study, we examined the role of IGF/IGFBP-3 signaling and its downstream and other associated events during chemoprevention of prostate cancer by green tea polyphenols in TRAMP mice. Our data demonstrated an increase in the levels of IGF-I, phosphatidylinositol 3'-kinase, phosphorylated Akt (Thr-308), and extracellular signal-regulated kinase 1/2 with concomitant decrease in IGFBP-3 in dorso-lateral prostate of TRAMP mice during the course of cancer progression, i.e., as a function of age. Continuous green tea polyphenol infusion for 24 weeks to these mice resulted in substantial reduction in the levels of IGF-I and significant increase in the levels of IGFBP-3 in the dorso-lateral prostate. This modulation of IGF/IGFBP-3 was found to be associated with an inhibition of protein expression of phosphatidylinositol 3'-kinase, phosphorylated forms of Akt (Thr-308) and extracellular signal-regulated kinase 1/2. Furthermore, green tea polyphenol infusion resulted in marked inhibition of markers of angiogenesis and metastasis most notably vascular endothelial growth factor, urokinase plasminogen activator, and matrix metalloproteinases 2 and 9. Based on our data, we suggest that IGF-I/IGFBP-3 signaling pathway is a prime pathway for green tea polyphenol-mediated inhibition of prostate cancer that limits the progression of cancer through inhibition of angiogenesis and metastasis.
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PMID:Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. 1557 82

To identify genes associated with insulin-like growth factor-I receptor (IGF-IR)-mediated cellular transformation, we isolated genes that are differentially expressed in R- cells (derived from the IGF-IR knockout mouse) and R+ cells (R- cells that overexpress the IGF-IR). From these, 45 genes of known function were expressed at higher levels in R+ cells and 22 were expressed at higher levels in R- cells. Differential expression was confirmed by Northern blot analysis of R+ and R- cells. Genes expressed more abundantly in R+ cells are associated with (1) tumour growth and metastasis including, betaigH3, mts1, igfbp5 protease, and mystique; (2) cell division, including cyclin A1 and cdk1; (3) signal transduction, including pkcdeltabp and lmw-ptp; and (4) metabolism including ATPase H+ transporter and ferritin. In MCF-7 cells IGF-I induced expression of two genes, lasp-1 and mystique, which could contribute to metastasis. Lasp-1 expression required activity of the PI3-kinase signalling pathway. Mystique was highly expressed in metastatic but not in androgen-dependent prostate cancer cell lines and Mystique overexpression in MCF-7 cells promoted cell migration and invasion. We conclude that genes identified in this screen may mediate IGF-IR function in cancer progression.
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PMID:Gene expression profiles in cells transformed by overexpression of the IGF-I receptor. 1594 Feb 54

IGF binding protein (IGFBP)-3 inhibits cell growth and promotes apoptosis by sequestering free IGFs. In addition IGFBP-3 has IGF-independent, proapoptotic, antiproliferative effects on prostate cancer cells in vitro. Expression of the large T-antigen (Tag) under the long probasin promoter (LPB) in LPB-Tag mice results in prostate tumorigenesis. To investigate the IGF-dependent and IGF-independent effects of IGFBP-3 on prostate tumor growth, we crossed LPB-Tag mice with cytomegalovirus (CMVBP-3) and phosphoglycerate kinase (PGKBP-3) mice that overexpress IGFBP-3 under the cytomegalovirus promoter and the phosphoglycerate kinase promoter, respectively, and also I56G/L80G/L81G-mutant IGFBP-3 (PGKmBP-3) mice that express I56G/L80G/L81G-IGFBP-3, a mutant, that does not bind IGF-I but retains IGF-independent proapoptotic effects in vitro. Prostate tumor size and the steady-state level of p53 were attenuated in LPB-Tag/CMVBP-3 and LPB-Tag/PGKBP-3 mice, compared with LPB-Tag/wild-type (Wt) mice. A more marked effect was observed in LPB-Tag/CMVBP-3, compared with LPB-Tag/PGKBP-3, reflecting increased levels of transgene expression in CMVBP-3 prostate tissue. No attenuation of tumor growth was observed in LPB-Tag/PGKmBP-3 mice during the early tumor development, indicating that the inhibitory effects of IGFBP-3 were most likely IGF dependent during the initiation of tumorigenesis. At 15 wk of age, epidermal growth factor receptor expression was increased in LPB-Tag/Wt and LPB-Tag/PGKmBP-3 tissue, compared with LPB-Tag/PGKBP-3. IGF receptor was increased in all transgenic mice, but pAkt expression, a marker of downstream IGF-I action, was increased only in LPB-Tag/Wt and LPB-Tag/PGKmBP-3. After 15 wk of age, a marked reduction in tumor growth was apparent in LPB-Tag/PGKmBP-3 mice, indicating that the IGF-independent effects of IGFBP-3 may be important in inhibiting tumor progression.
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PMID:Insulin-like growth factor (IGF) binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms. 1661 54

Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1alpha versus HIF-2alpha to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.
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PMID:Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. 1677 2

The mammalian insulin-like growth factor (IGF)-II/cation-independent mannose 6-phosphate receptor (IGF2R) binds IGF-II with high affinity. By targeting IGF-II to lysosomal degradation, it plays a role in the maintenance of correct IGF-II levels in the circulation and in target tissues. Loss of IGF2R function is associated with tumor progression; therefore, the IGF2R is often referred to as a tumor suppressor. The interaction between IGF2R and IGF-II involves domains 11 and 13 of the 15 extracellular domains of the receptor. Recently, a hydrophobic binding region was identified on domain 11 of the IGF2R. In contrast, relatively little is known about the residues of IGF-II that are involved in IGF2R binding and the determinants of IGF2R specificity for IGF-II over the structurally related IGF-I. Using a series of novel IGF-II analogues and surface plasmon resonance assays, this study revealed a novel binding surface on IGF-II critical for IGF2R binding. The hydrophobic residues Phe(19) and Leu(53) are critical for IGF2R binding, as are residues Thr(16) and Asp(52). Furthermore, Thr(16) was identified as playing a major role in determining why IGF-II, but not IGF-I, binds with high affinity to the IGF2R.
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PMID:A novel binding site for the human insulin-like growth factor-II (IGF-II)/mannose 6-phosphate receptor on IGF-II. 1747 26

Epidemiological studies suggest that the GH/IGF-I axis may promote human cancers. Animal models in which the GH/IGF-I axis can be controlled may be helpful in elucidating the role of these hormones during mammary cancer progression. Beginning at 3 or 5 wk of age, spontaneous dwarf rats (Gh(dr/dr)), which lack GH and have very low serum IGF-I, were treated with either rat or bovine GH twice daily. Other Gh(dr/dr) rats received vehicle, and wild-type Sprague Dawley rats (Gh(+/+), parent strain to SDR) received vehicle. One week later, all rats were exposed to a single injection of N-methyl-N-nitrosourea. Body weight gain and serum IGF-I levels were similar in Gh(+/+) and GH-treated Gh(dr/dr) rats. Furthermore, mammary tumor incidence, latency, and multiplicity were similar in Gh(+/+) and GH-treated Gh(dr/dr) rats. Vehicle-treated Gh(dr/dr) rats developed no tumors. Once advanced (> or =1 cm(3)) mammary cancers were established in GH-treated Gh(dr/dr) rats, GH treatments were halted and nearly all tumors regressed completely within 2 wk. Tumor regression was associated with loss of phospho-signal transducer and activator of transcription-3, but not alterations in IGF-I, IGF-I receptor, or GH receptor. These results demonstrate that Gh(dr/dr) rats, which are nearly refractory to mammary carcinogenesis, can be made vulnerable by restoring GH and IGF-I. Furthermore, advanced rat mammary cancers are dependent on GH and/or IGF-I for their survival. Therefore, therapeutics that target either GH or IGF-I may be effective at treating even advanced mammary cancers.
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PMID:Advanced rat mammary cancers are growth hormone dependent. 1758 69

Prostate carcinomas frequently express estrogen receptors (ER), irrespective of androgen receptor (AR) expression; however, the role of ERs and estrogens in prostate cancer is controversial. We found that 17beta-estradiol (E(2)) is able to markedly up-regulate insulin-like growth factor (IGF)-I receptor (IGF-IR) mRNA and protein expression in both AR-positive (LNCaP cells) and AR-negative (PC-3 cells) prostate cancer cells. This effect occurs not only via ERalpha but also via ERbeta stimulation and is specific for IGF-IR because it does not involve the cognate insulin receptor. IGF-IR up-regulation is associated with increased IGF-IR phosphorylation and with increased mitogenic and motogenic activities in response to IGF-I. IGF-IR up-regulation by E(2) does not require ER binding to DNA and is poorly sensitive to antiestrogen blockade, whereas it is associated with the activation of cytosolic kinase cascades involving Src, extracellular signal-regulated kinase (ERK)-1/2, and, to a lesser extent, phosphatidylinositol 3-kinase and is sensitive to the inhibition of these kinases. In conclusion, our data indicate that estrogens may contribute to IGF system deregulation in prostate cancer through the activation of a nongenotropic pathway. Estrogens may have a role, therefore, in tumor progression to androgen independence. Inhibition of the IGF-IR or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in prostate cancer.
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PMID:17beta-estradiol up-regulates the insulin-like growth factor receptor through a nongenotropic pathway in prostate cancer cells. 1787 36


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