Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin-like growth factor II (IGF-II) is involved in embryonic growth. Modifications of its expression might play a role in the development of primary liver cancer in humans and woodchucks. In the liver, little information is available on the cell types involved in its synthesis. We have investigated the expression of IGF-II as well as IGF-II, IGF-I and insulin receptor mRNAs in non parenchymal liver cell preparations in rats of various ages. The results indicate that Kupffer cells, endothelial cells and fat-storing cells express both IGF-II and the three different receptor mRNAs. Furthermore, a switch from a fetal to an adult IGF-II mRNA profile was obtained in the different cell preparations. Therefore, our results indicate that regulation of IGF-II gene expression can be analyzed through these isolated liver cell preparations. These results might also be important in investigating the potential role of IGF-II in liver carcinogenesis.
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PMID:Expression of insulin-like growth factor II (IGF-II) and IGF-II, IGF-I and insulin receptors mRNAs in isolated non-parenchymal rat liver cells. 131 Jul 5

Insulin-like growth factor (IGF) I and IGF-II were measured by radioimmunoassay in the sera of seven patients with acromegaly, 36 normal control subjects, 15 patients with chronic hepatitis, 15 patients with cirrhosis, 25 patients with hepatocellular carcinomas (HCCs) who did not have hypoglycemia, 20 patients with HCCs who did have hypoglycemia, and 10 patients with metastatic liver tumors. Both IGF-I and IGF-II levels decreased as liver disease progressed from the normal control stage to chronic hepatitis and cirrhosis, and both levels reflected the severity of liver disease. Patients with HCCs who had hypoglycemia had relatively higher IGF-II levels in their sera in comparison with those who did not have hypoglycemia (272 +/- 167.5 ng/ml vs 110.4 +/- 85.9 ng/ml [mean +/- SD], p less than 0.0005), despite the fact that those with hypoglycemia had more advanced liver cancer and had lower IGF-I levels in sera (16.7 +/- 14.1 ng/ml vs 46.8 +/- 47.9 ng/ml, p less than 0.002). It is possible that a labile IGF-II material is produced by the cancer cells of patients with hypoglycemia. This factor is reactive to the IGF-II receptor and partially cross-reacts with an antibody to IGF-II; it accounted for the mildly elevated levels of serum IGF-II. Hypoglycemia may be an integral effect of relatively elevated IGF-II like material and an advanced liver cancer. Also, higher serum alpha-fetoprotein (AFP) levels were more frequently found in patients with hypoglycemia who had relatively elevated IGF-II levels and short survivals.
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PMID:Radioimmunoassay of serum IGF-I and IGF-II in patients with chronic liver diseases and hepatocellular carcinoma with or without hypoglycemia. 246 May 70

Hepatocellular carcinoma (HCC) is a common malignancy, but treatment outcomes have generally remained poor. Specific factors important for the pathogenesis of HCC are incompletely understood. Insulin-like growth factors (IGFs) are potent autocrine and paracrine mitogens for liver cancer cell proliferation, and their bioactivity is reduced by IGF-binding protein 3 (IGFBP-3). In the present study, we report that IGFBP-3 protein levels were either undetectable (28.5%) or low (71.5%) in human HCC samples examined compared with matched non-neoplastic liver tissue by Western blotting. IGFBP-3 was localized to nontumor liver cells by immunohistochemistry with greater immunointensity than neoplastic liver cells. Levels of type I receptor (IGF-IR) were found to be low in approximately 39% of human HCC samples examined compared with matched nontumor tissues. IGF-II was overexpressed in 32%, whereas IGF-I expression was decreased in 100% of HCC samples. In vitro studies revealed that IGF-I and IGF-II induced HepG2 cell proliferation in a dose-dependent manner. Treatment of HepG2 cells with either human recombinant IGFBP-3 (hrIGFBP-3) or IGF-II antibody led to a significant reduction in cell proliferation. Cotreating these cells with hrIGFBP-3 significantly attenuated the mitogenic activity of IGF-I. IGF-I-induced phosphorylation of IGF-IR beta subunit, IRS-1, mitogen-activated protein kinase, Elk-1, and Akt-1 as well as phosphatidylinositol 3'-kinase activity was significantly attenuated when hepG2 cells were pretreated with hrIGFBP-3. Our data indicate that loss of autocrine/paracrine IGFBP-3 loops may lead to HCC tumor growth and suggest that modulating production of the IGFs, IGFBP-3, and IGF-IR may represent a novel approach in the treatment of HCC.
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PMID:A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. 1195 12

Insulin-like growth factor binding protein-1 (IGFBP-1) is synthesized in the liver and regulates the mitogenic effects of the insulin-like growth factors (IGFs). The evidence that IGFBP-1 plays a role in hepatocarcinogenesis, however, is equivocal. We have, therefore, investigated the development of preneoplastic hepatic lesions in transgenic mice in which the human IGFBP-1 gene is under the control of the mouse metallothionein promoter. The lesions were induced by treating 15-d-old male mice with a single intraperitoneal injection of 5 mg/kg diethylnitrosamine (DENA). Lesions were scored when the mice were 28 wk of age. Quantitative microscopy of liver sections revealed that significantly fewer transgenic mice treated with zinc to activate the transgene had focal lesions compared to either transgenic mice not treated with zinc or wild-type mice treated with zinc (36.4% versus 85.7% and 83.3%, respectively, P < 0.05 in each case). Zinc-treated transgenic mice also had significantly fewer lesions per liver (11.5 +/- 5.0 versus 74.7 +/- 18.4 and 59.4 +/- 15.6, respectively, P < 0.01 in each case) and a smaller percentage of liver volume occupied by lesions (0.2 +/- 0.1 versus 1.4 +/- 0.3 and 1.1 +/- 0.4 respectively, P < 0.05 in each case). Immunohistochemical staining showed that both IGF-I and IGF-II were overexpressed in most of the lesions. These results show that expression of the IGFBP-1 transgene leads to a marked inhibition of hepatic preneoplasia, possibly by decreasing the mitogenic activity of IGF-I and/or IGF-II. This study adds new evidence to the notion that the IGF axis plays an important role in liver cancer development.
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PMID:Insulin-like growth factor binding protein-1 over-expression in transgenic mice inhibits hepatic preneoplasia. 1261 36

We have previously shown that LCC6 wild-type (WT) cells, a metastatic variant of MDA-MB-435 cancer cells originally derived from a breast cancer patient, exhibit enhanced motility in response to IGF-I compared with the parent MDA-MB-435 cells. To further understand the role of the type I insulin-like growth factor (IGF) receptor (IGF1R) in cancer metastasis we inhibited signaling via IGF1R using a C-terminal-truncated IGF1R. The truncated receptor retains the ligand binding domain but lacks the autophosphorylated tyrosine residues in the carboxyl terminus. Cells stably transfected with this truncated receptor (LCC6-DN cells) overexpressed the truncated IGF1R messenger RNA nearly 50-fold over endogenous receptor. The truncated receptor in the LCC6-DN cells behaved in a dominant negative manner to inhibit endogenous IGF1R activation by IGF-I. Compared with the LCC6-WT cells, LCC6-DN cells failed to phosphorylate the adaptor proteins insulin receptor substrate-1 and -2 in response to IGF-I and did not activate Akt after exposure to IGF-I. Unlike LCC6-WT cells, LCC6-DN cells did not show enhanced motility in response to IGF-I. To assay for metastasis, LCC6-WT and LCC6-DN cells were injected into the mammary fat pads of mice, and the primary xenograft tumors were removed after 21 days. Mice sacrificed 5 weeks later showed multiple lung metastases derived from LCC-WT xenografts, whereas mice harboring LCC6-DN xenografts showed no lung metastases. Our data show that IGF1R can regulate several aspects of the malignant phenotype. In these cells, metastasis but not proliferation requires IGF1R function.
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PMID:A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. 1461 89

Insulin-like growth factors (IGFs) are mitogens for numerous types of cells including cancer cells. The aim of this work was to analyze some of the components of the IGF system to assess which could be potential clinical biomarkers for monitoring patients diagnosed with liver cancer. Compared to healthy persons, patients with liver cancer had a lower concentration of IGF-I and a higher concentration of IGFBP-1, whereas the concentrations of IGF-II and IGFBP-3 remained unchanged. The IGF-I:IGFBP-3 ratio decreased in patients with cancer, while the IGF-II:IGFBP-1 ratio was not altered. Patients with primary carcinoma and those scheduled for surgery had lower IGF-I and higher IGF-II and IGFBP-1 concentrations than patients with secondary carcinoma and those not eligible for surgery. It may be postulated that a liver with primary cancer is induced to increase IGF-II and IGFBP-1 synthesis more than a liver involved in metastatic response. Similarly, in patients eligible for liver surgery an increase in IGF-II may reflect a gradual change in the concentration associated with a different stage of disease. As increased synthesis of certain IGFBPs is necessary to compensate decreased production of the others or increased IGF production, determination of serum IGF-II, IGFBP-1 and their ratio may aid in estimating the compensatory capacity of the liver affected by cancer.
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PMID:Association of elevated IGFBP-1 with increased IGF-II concentration in patients with carcinoma of the liver. 1919 70

Elevated expression of insulin-like growth factor-II (IGF-II) is frequently observed in a variety of human malignancies, including breast, colon, and liver cancer. As IGF-II can deliver a mitogenic signal through both IGF-IR and an alternately spliced form of the insulin receptor (IR-A), neutralizing the biological activity of this growth factor directly is a potential alternative option to IGF-IR-directed agents. Using a Fab-displaying phage library and a biotinylated precursor form of IGF-II (1-104 amino acids) as a target, we isolated Fabs specific for the E-domain COOH-terminal extension form of IGF-II and for mature IGF-II. One of these Fabs that bound to both forms of IGF-II was reformatted into a full-length IgG, expressed, purified, and subjected to further analysis. This antibody (DX-2647) displayed a very high affinity for IGF-II/IGF-IIE (K(D) value of 49 and 10 pmol/L, respectively) compared with IGF-I (approximately 10 nmol/L) and blocked binding of IGF-II to IGF-IR, IR-A, a panel of insulin-like growth factor-binding proteins, and the mannose-6-phosphate receptor. A crystal complex of the parental Fab of DX-2647 bound to IGF-II was resolved to 2.2 A. DX-2647 inhibited IGF-II and, to a lesser extent, IGF-I-induced receptor tyrosine phosphorylation, cellular proliferation, and both anchorage-dependent and anchorage-independent colony formation in various cell lines. In addition, DX-2647 slowed tumor progression in the Hep3B xenograft model, causing decreased tumoral CD31 staining as well as reduced IGF-IIE and IGF-IR phosphorylation levels. Therefore, DX-2647 offers an alternative approach to targeting IGF-IR, blocking IGF-II signaling through both IGF-IR and IR-A.
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PMID:A human monoclonal antibody against insulin-like growth factor-II blocks the growth of human hepatocellular carcinoma cell lines in vitro and in vivo. 2051 53