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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of insulin-like growth factor binding proteins (IGFBP) with special reference to human IGFBP-1 was evaluated in five endometrial adenocarcinoma cell lines (HEC 1A, HEC 1B, KLE, RL952 and AN3CA) in continuous culture. Two of the cell lines (HEC 1B and KLE) produced immunoreactive IGFBP-1. The production was inhibited by clomiphene and progesterone, whereas estrogen, cortisol and insulin had no effect on IGFBP-1 secretion. The two cell lines which secreted immunoreactive IGFBP-1 also had IGF-I receptors, whereas the cell lines RL952 and AN3CA, not producing IGFBP-1, had no saturable IGF membrane binding sites. IGF-I receptor binding to HEC 1B and KLE cells was inhibited in the presence of purified IGFBP-1. In addition to IGFBP-1, the endometrial cancer cells secreted several other forms of IGFBPs as determined by cross-linking. Immunoprecipitation of IGF-BP complexes with a polyclonal antiserum against IGFBP-3 indicated that all cell lines secreted binding proteins antigenically related to IGFBP-3 with molecular weights ranging from 20 to 39 kDa.
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PMID:Human endometrial adenocarcinoma cell lines HEC 1B and KLE secrete insulin-like growth factor binding protein-1 and contain IGF-I receptors. 171 Sep 98

Insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins (IGFBPs) were examined in Ishikawa endometrial cancer cells. Our findings suggest that about 95% of [125I]IGF-I is bound to membrane-associated IGFBPs rather than to IGF-I receptors. Specifically, [125I]IGF-I binding to cell membranes could be completely displaced by cold IGF-I or IGF-II, but not by insulin, suggesting that binding was primarily due to IGFBPs. This was confirmed by using [125I]des-(1-3)IGF-I as the ligand. Des-(1-3) IGF-I binds with high affinity to IGF-I receptors, but with markedly lower affinity to IGFBPs. [125I]Des-(1-3)IGF-I bound to Ishikawa cells was displaced by IGF-I, IGF-II, and insulin. These results suggest that measuring IGF-I receptor levels using labeled IGF-I may be misleading. Accordingly, we evaluated the differential binding of [125I]IGF-I and [125I]des-(1-3)IGF-I to study the involvement of the IGF system in the stimulation of Ishikawa cell growth by estradiol. IGF-I stimulates Ishikawa cell proliferation, but at low concentrations, and this stimulation is largely dependent on the presence of estradiol. Estradiol caused a 2.5-fold increase in IGF-I receptor levels. Moreover, estradiol reduced soluble IGFBP levels, presumably increasing the availability of IGFs for their receptors. This elevation in IGF-I receptor levels and the decrease in IGFBP levels were accompanied by a 3.5-fold increase in IGF-I receptor messenger RNA and a 2.5-fold decrease in IGFBP messenger RNAs. These experiments suggest that estradiol sensitizes endometrial cancer cells to the effects of IGFs by simultaneously elevating receptor levels and decreasing (potentially inhibitory) IGFBP levels.
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PMID:Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol. 775 Apr 75

The involvement of IGFs in growth regulation of the Ishikawa endometrial tumor cell line and the possible interference of LH-RH analogues with a potential autocrine or paracrine loop involving IGFs was evaluated. The mitogenic effects of IGF-I, IGF-II, and insulin were compared. IGF-I was found to be 3-fold more potent than IGF-II and 30-fold more potent than insulin, suggesting that the effects of these growth factors are mediated by the IGF-I receptor. Ishikawa endometrial cancer cells secrete IGF-II, but not IGF-I, and insulin (1 microM) stimulates IGF-II release. The LH-RH antagonist [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]-GnRH (SB-75, CETRORELIX) inhibited basal and IGF-induced growth. Moreover, this antagonist almost completely inhibited IGF-II release from Ishikawa cells, while having no significant effect on the number or affinity of IGF-I binding sites. Inhibition of IGF-II release occurred at a lower SB-75 concentration than that needed for a reduction in cell number. The ED50 of SB-75 for IGF-II release was 0.3 microM as compared to 1.5 microns concentration which is required for reduction in cell number, suggesting that inhibition of growth factor release precedes cell growth inhibition. We conclude that the LH-RH antagonist SB-75 can inhibit the growth of endometrial cancer cells by interfering with the autocrine action of IGF-II and also by directly inhibiting the growth-stimulatory effects of IGFs, probably through effects on a post-receptor mechanism.
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PMID:Regulation of endometrial cancer cell growth by insulin-like growth factors and the luteinizing hormone-releasing hormone antagonist SB-75. 826 21

The function of cell surface-associated insulin-like growth factor-binding proteins (IGFBPs) is controversial. Both inhibition and facilitation of IGF action as well as IGF-independent effects have been reported. We examined the influence of endogenous cell surface-associated IGFBPs on IGF-I receptor (IGF-IR) function in Ishikawa endometrial cancer cells by comparing the effects of IGF-I and its truncated analog des-(1-3)-IGF-I on several components of the IGF-IR signal transduction pathway in the absence of significant amounts of soluble IGFBPs. IGF-I and des-(1-3)-IGF-I are known to have similar affinities for IGF-IR, although the affinity of des-(1-3)-IGF-I for IGFBPs is greatly reduced. Here we show that the two ligands were equipotent not only in IGF-IR binding but also in receptor activation in NIH 3T3 cells overexpressing IGF-IR and possessing a relatively small number of cell surface-associated IGFBPs. In contrast, des-(1-3)-IGF-I manifested a remarkably higher potency as compared with IGF-I in inducing short and middle term cellular responses in IGF-IR-transfected Ishikawa endometrial cancer cells possessing a high number of both the receptor and the cell membrane-bound IGFBP-3. Thus, this difference in the effects of IGF-I and des-(1-3)-IGF-I can be attributed to the attenuation of IGF-I-mediated IGF-IR signaling by membrane-bound IGFBP-3.
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PMID:Membrane-associated insulin-like growth factor-binding protein-3 inhibits insulin-like growth factor-I-induced insulin-like growth factor-I receptor signaling in ishikawa endometrial cancer cells. 919 61

While the role of steroid hormones in the regulation of endometrial proliferation and differentiation is well established, the effects of growth factors and their receptors in normal and neoplastic endometrium remain a matter of debate. Previous studies have documented the positive effects of insulin-like growth factor-I (IGF-I) on epithelial cell proliferation and the active production of this growth factor in endometrial tissues. In view of decreased expression of transforming growth factor-beta1 (TGF-beta1), an antagonist of IGF-I, in endometrial carcinoma, we investigated the expression of IGF-I, at both the mRNA and protein levels, and the immunoreactivity for type I IGF-I receptor in 30 formalin-fixed, paraffin-embedded tissue samples of normal and neoplastic endometrium, in order to possibly clarify the role of IGF-I in endometrial proliferation and differentiation. Our results demonstrate a reduced expression of IGF-I mRNA in endometrial carcinomas compared with non-neoplastic tissues, despite equivalent immunohistochemical expression of IGF-I and IGF-I receptor. Our data suggest that IGF-I and its corresponding receptor may not be directly involved in endometrial cancer cell proliferation and differentiation in vivo, though other components of the IGF-I system (e.g., IGF binding proteins) may affect endometrial malignant transformation and tumor progression.
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PMID:Insulin-like growth factor-I expression in normal and diseased endometrium. 993 98

The inappropriate expressions of insulin-like growth factors (IGF-I and II) and IGF-I receptor (IGF-IR) are implicated in the malignant growth of many cancers. To determine changes, if any, in the levels of expression of IGFs and IGF receptor genes in neoplastic endometrium, relative to normal endometrium, the mRNA levels of IGF-I and II and of IGF-IR and IIR were measured in samples of endometrial carcinomas (EC) and normal endometrium, through all phases of the menstrual cycle, by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assays. In normal endometrium, the mRNA levels of IGF-I were elevated in the proliferative and early secretory phases. The IGF-II mRNAs were relatively high in the proliferative phase, but unaltered through early and late secretory phases. Significantly elevated levels of IGF-II transcripts were observed during the menstrual phase, suggesting a possible role of IGF-II in endometrial regeneration. A positive correlation between the levels of IGF-I and IGF-IR mRNAs, apparent in the samples of normal endometrium, was not observed in endometrial carcinomas. The IGF-IR and IIR mRNA levels were elevated in endometrial carcinoma samples. On the other hand, the IGF-I and II mRNA levels were conspicuously low in many carcinoma samples, which were not associated with hyperplasia (type II EC), but relatively elevated in two other carcinoma samples, associated with adenomatous hyperplasia (type I EC). These results albeit with few samples suggest the possibility that the overexpressed receptor, IGF-IR, could be activated differently in two types of endometrial carcinomas, namely ligand-dependently in type I ECs and ligand-independently in type II ECs.
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PMID:Discordant expression of insulin-like growth factors and their receptor messenger ribonucleic acids in endometrial carcinomas relative to normal endometrium. 1045 50

Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-IR) can assemble heteromerically as a hybrid insulin/IGF-I receptor (hybrid-R) in tissues that express both molecules. There is little information about hybrid-R in endometrial carcinoma, in which both IR and IGF-IR are frequently overexpressed. We used immunoprecipitation to detect hybrid-R expression in two endometrial carcinoma cell lines: HEC-1a, which has low estrogen receptor (ER) expression, and Ishikawa, which is positive for ER expression. To explore the role of hybrid-R in endometrial carcinoma cells, we examined phosphorylation of extracellular signal-regulated kinase (ERK1/2), which is a key molecule in the mitogen-activated protein kinase (MAPK) pathway. The effect of inhibiting IGF-I, IGF-II, and insulin on cell cycle progression and apoptosis was assessed by flow cytometry. Both cell lines expressed hybrid-R, and HEC-1a cells had higher expression levels than did Ishikawa cells. IGF-I induced ERK1/2 phosphorylation in HEC-1a cells mainly through hybrid-R; in Ishikawa cells, this effect was mediated only in part by hybrid-R. Insulin stimulated ERK1/2 phosphorylation partly through hybrid-R in HEC-1a cells, but not in Ishikawa cells. Both IGFs and insulin increased cellular DNA content in the S phase of the cell cycle in HEC-1a through hybrid-R. In contrast, in Ishikawa cells, only insulin enhanced DNA content in S phase through hybrid-R. Both IGFs and insulin significantly decreased apoptosis in HEC-1a cells through hybrid-R, and a similar but moderate effect was observed in Ishikawa cells. Hybrid-R, which is present in endometrial carcinoma cells, may have an important role in mediating IGF- and insulin-induced cell growth and in preventing apoptosis.
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PMID:The expression and role of hybrid insulin/insulin-like growth factor receptor type 1 in endometrial carcinoma cells. 2062 May 97

A correlation between components of the insulin-like growth factor (IGF) system and endometrial cancer risk has been shown in recent studies. The antitumor action of vorinostat, a histone deacetylase inhibitor, involves changes in the expression of specific genes via acetylation of histones and transcription factors. The aim of this study was to establish whether vorinostat can modify the expression of specific genes related to the IGF-I receptor (IGF-IR) signaling pathway and revert the transformed phenotype. Human endometrioid (Type I, Ishikawa) and uterine serous papillary (Type II, USPC-2) endometrial cancer cell lines were treated with vorinostat in the presence or absence of IGF-I. Vorinostat increased IGF-IR phosphorylation, produced acetylation of histone H3, up-regulated pTEN and p21 expression, and reduced p53 and cyclin D1 levels in Ishikawa cells. Vorinostat up-regulated IGF-IR and p21 expression, produced acetylation of histone H3, and down-regulated the expression of total AKT, pTEN and cyclin D1 in USPC-2 cells. Of interest, IGF-IR activation was associated with a major elevation in IGF-IR promoter activity. In addition, vorinostat treatment induced apoptosis in both cell lines and abolished the anti-apoptotic activity of IGF-I both in the absence or presence of a humanized monoclonal IGF-IR antibody, MK-0646. Finally, vorinostat treatment led to a significant decrease in proliferation and colony forming capability in both cell lines. In summary, our studies demonstrate that vorinostat exhibits a potent apoptotic and anti-proliferative effect in both Type I and II endometrial cancer cells, thus suggesting that endometrial cancer may be therapeutically targeted by vorinostat.
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PMID:The mechanism of action of the histone deacetylase inhibitor vorinostat involves interaction with the insulin-like growth factor signaling pathway. 2193 26

The role of the insulin-like growth factors (IGF) in endometrial cancer has been well established. The IGF-I receptor (IGF-IR), which mediates the biological actions of IGF-I, is usually overexpressed in endometrial tumours. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Mutation of the p53 gene appears early in the course of the disease and is considered a key event in the initiation of USC. The aim of the present study was to evaluate the potential interactions between p53 and the IGF-IR in USC. In addition, we investigated the role of p53 as a biomarker in IGF-IR targeted therapies. Immunohistochemical analysis in a collection of 35 USC specimens revealed that IGF-IR is highly expressed in primary and metastatic USC. Likewise, p53 was expressed in 85.7% of primary tumours and 100% of metastases. A significant negative correlation between p53 expression and survival was noticed. In addition, using USC-derived cell lines we provide evidence that p53 regulates IGF-IR gene expression via a mechanism that involves repression of the IGF-IR promoter. We show that the mechanism of action of p53 involves interaction with zinc finger protein Sp1, a potent transactivator of the IGF-IR gene. Finally, we demonstrate that USC tumours overexpressing p53 are more likely to benefit from anti-IGF-IR therapies. In summary, we provide evidence that p53 regulates IGF-IR gene expression in USC cells via a mechanism that involves repression of the IGF-IR promoter. The interplay between the p53 and IGF-I signalling pathways is of major basic and translational relevance.
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PMID:p53 Regulates insulin-like growth factor-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy. 2203 26

Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.
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PMID:Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners. 2362 Jul 61


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