UMLS:C0476089 - FACTA Search

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

The insulin-like growth factor (IGF) system is thought to function as a mediator of steroid hormone actions in the endometrium. IGFs (IGF-I and IGF-II) are also potent mitogens in endometrial cancer. The biological actions of IGFs are modulated by specific binding proteins (IGFBP)--6 cloned and sequenced so far--which may either inhibit or enhance the effects of IGF at the cellular level. In the endometrium, IGFBP-1 gene expression is stimulated by progesterone and inhibited by insulin, while IGFBP-1 inhibits the mitogenic action of IGF-I. In this study, we used a quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to investigate IGFBP-1, IGFBP-2, IGFBP-4, IGFBP-5 and IGFBP-6 gene expression in endometrial cancer tissues. Endometrial cancer tissue samples were collected from 20 women (aged 54-79 yrs) with stage I to II well-differentiated endometrial adenocarcinoma. Samples of normal endometrium (n = 14) obtained from women undergoing tubal ligation in various phases of the menstrual cycle, and normal early-pregnancy endometrium (decidua) were studied for comparison. In endometrial cancer tissues, the IGFBP-1 mRNA was undetectable or minimally expressed when studied by RT-PCR. The mean (+ SD) levels of IGFBP-2 and IGFBP-4 and IGFBP-5 mRNAs in endometrial cancer tissues did not differ from those in normal endometrium, in which no cyclic variation was observed, suggesting that the genes encoding IGFBP-2, IGFBP-4 and IGFBP-5 are not hormonally regulated in the endometrium. The IGFBP-6 mRNA expression showed a significant cyclic variation in normal endometrium, with low levels in late-proliferative and early- to mid-secretory phases and high expression in late-secretory and early-proliferative phases. In endometrial cancer tissues, the mean IGFBP-6 mRNA level was similar to that in cycling endometrium during the peri-ovulatory period. In summary, a continuous stimulation of the endometrial epithelial cells by IGFs with suppressed IGFBP-1 expression may lead to an imbalance in the IGF system of the endometrium and trigger an uncontrolled cell proliferation, ultimately resulting in malignant transformation.
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PMID:Suppressed expression of insulin-like growth factor binding protein-1 mRNA in the endometrium: a molecular mechanism associating endometrial cancer with its risk factors. 752 16

In uterine tissue, estrogen regulates various components of the insulin-like growth factor system; however, there are few suitable in vitro systems to examine these effects. Here we have examined the effects of 17-beta estradiol (E2) on expression and synthesis of insulin-like growth factors (IGF-I and IGF-II) and the insulin-like growth factor binding proteins (IGFBPs) by Ishikawa human endometrial cancer cells. Using a semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, we demonstrated that both E2 and 4-hydroxy-tamoxifen (OHT) enhanced IGF-I expression but had no effect on IGF-II expression. The pure antiestrogen ICI 182,780 had no effect on IGF-I expression and partially blocked the E2 and OHT effect on IGF-I expression. The effect of epidermal growth factor (EGF), which is able to mimic some of the effects of E2 in Ishikawa cells and uterine tissue, was also examined. EGF, unlike E2, did not increase IGF-I expression but rather resulted in a significant decrease in IGF-I messenger RNA (mRNA) levels. EGF also resulted in a small, nonsignificant increase in IGF-II mRNA levels. IGFBP-3, -5, and -6 mRNAs were detected by Northern blot analyses of Ishikawa cells RNA. However, only IGFBP-3 was consistently detected by ligand blotting of conditioned medium. E2 had no significant effect on expression of any of the binding proteins, whereas EGF increased IGFBP-5 mRNA levels. These data provide the first in vitro demonstration of regulation of IGF-I expression by E2. The Ishikawa cell line may provide a useful model to further investigate the molecular mechanisms underlying E2 regulation of IGF-I expression. Furthermore, we have demonstrated a clear dissociation of the effects of E2 and EGF on IGF-I expression in this cell line.
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PMID:Expression of insulin-like growth factors and their binding proteins in the estrogen responsive Ishikawa human endometrial cancer cell line. 752 33

Insulin is a major regulator of circulating insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), suppressing the hepatic production of IGFBP-1. Postmenopausal age, obesity, hypertension, and impaired glucose tolerance, which are known risk factors for endometrial cancer, are all associated with hyperinsulinemia and insulin resistance. In this study, we investigated the relationship among serum insulin, glucose, insulin-like growth factors (IGF-I and IGF-II), and IGFBP-, -2, and -3 in 32 nondiabetic postmenopausal women with endometrial cancer and in 18 healthy controls. The mean fasting levels of glucose and insulin were higher, whereas the mean basal IGF-I, IGF-II, and IGFBP-3 levels were lower in the endometrial cancer patients than in the healthy control subjects. The mean fasting IGFBP-1 and IGFBP-2 levels did not differ between the groups, and no correlation was found between fasting insulin and IGFBP-1 concentrations or between insulin and IGFBP-2 concentrations in either of the study groups. During an oral glucose tolerance test, the mean glucose levels at 1 and 3 h as well as the mean insulin level at 3 h were significantly higher in the endometrial cancer patients than in the controls, and the area under the glucose curve was larger in the first group. An oral glucose load resulted in a similar fall in serum IGFBP-1 levels in endometrial cancer patients and controls (51% and 55% at 3 h). When the cancer patients were divided into two subgroups according to the body mass index (kilograms per m2), the obese group had higher glucose and insulin indices than the nonobese group. No difference was found by the same measures in healthy controls. The fasting serum IGFBP-1 levels tended to be lower in the obese than in the normal weight subjects, but the difference did not reach statistical significance. In summary, these results provide preliminary evidence that the inverse relation between fasting insulin and IGFBP-1, well established in children and young adults, disappears in elderly women, although short term suppression by insulin still occurs. Further, our data indicate that in addition to carbohydrate metabolism, postmenopausal women with endometrial cancer have alterations in their circulating IGF system compared to controls.
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PMID:Relationship between carbohydrate metabolism and serum insulin-like growth factor system in postmenopausal women: comparison of endometrial cancer patients with healthy controls. 768 14

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

Growth factors and related peptides are believed to mediate and modulate the actions of hormones at their target tissues through autocrine/paracrine mechanisms. Endometrial stromal cells produce insulin-like growth factors I and II (IGF-I and IGF-II) as well as the high-affinity IGF binding proteins (IGFBPs), whereas epithelial cells and, in a lesser amount, also stromal cells contain cell membrane receptors for IGFs. IGFs have proliferative, differentiative and metabolic effects. Estrogen stimulates IGF-I gene expression in the endometrium, and IGF-I is assumed to mediate estrogen action. IGF-II gene expression is associated with endometrial differentiation. All six high-affinity IGFBPs are expressed in human endometrium, the most abundant being IGFBP-1. This is secreted by predecidualized/decidualized endometrial stromal cells in late secretory phase endometrium and pregnancy decidua, i.e. under the action of progesterone. The primary negative regulator of IGFBP-1 expression is insulin, by inhibiting IGFBP-1 transcription. IGFBP-1 inhibits the receptor binding and biological actions of IGF-I in the endometrium and in cultured human trophoblastic cells. These findings support the view that the IGF system has autocrine and paracrine functions in the regulation of endometrial proliferation and differentiation. After implantation, decidual IGFBP-1 may regulate IGF actions at the embryo-endometrial interface, since trophoblast cells contain IGF receptors and express IGF-II, but do not express IGFBP-1. Clinical conditions that are known to increase the risk of endometrial cancer are all characterized by the absence of IGFBP-1. Thus, like unopposed estrogen, unopposed IGF-I action may also lead to uncontrolled endometrial proliferation and favor the development of endometrial cancer. The measurement of mRNAs encoding the IGF system might provide a novel tool to evaluate the endometrial response to endogenous and exogenous estrogens and progestins at the molecular level.
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PMID:Insulin-like growth factors in endometrial function. 1006 65

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

Adiponectin is a hormone secreted exclusively by adipocytes, and obesity is an established risk factor for endometrial cancer. We have, thus, evaluated the association of adiponectin with the occurrence of endometrial cancer. Questionnaire information and blood samples were taken before treatment from 84 women with newly diagnosed, histologically confirmed endometrial cancer and 84 control women who were admitted for minor gynecologic problems, mainly pelvic prolapse. Adiponectin levels were measured by immunoassay. The results were analyzed through multiple logistic regression and controlled for known risk factors for endometrial cancer, leptin, as well as major components of the IGF system (IGF-I, IGF-II, and IGF-binding protein 3). Among control women, there was no significant association of adiponectin with age or parity. Although there was no association of adiponectin with endometrial cancer among women 65 yr or older, there was an inverse, fairly strong, and statistically significant inverse association among younger women. Among women younger than 65 yr, an increase of adiponectin by 1 SD was associated with a more than 50% reduction of the risk for endometrial cancer [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.24-0.81], even after controlling for body mass index and other potential confounders. Among all women, the adjusted OR for a 1 SD increase in adiponectin was not significant (OR, 0.78; 95% CI, 0.56-1.10) but was significant for a one quintile increase in adiponectin (OR, 0.74; 95% CI, 0.56-0.97). In women younger than 65 yr, among whom obesity represents a powerful risk factor for endometrial cancer, adiponectin is inversely and significantly related to the risk of this disease. This association is independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known endometrial cancer risk factors. Future studies are needed to prove causality and provide insight on both the mechanism of action of this hormone and its potential role in endometrial cancer.
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PMID:Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. 1262 74

Antagonists of GHRH are being developed for the treatment of various cancers. In this study we investigated in vivo and in vitro the effects of the GHRH antagonist MZ-J-7-118 and its mechanism of action in HEC-1A human endometrial cancer. Treatment of nude mice bearing HEC-1A xenografts with 10 mug/d MZ-J-7-118 for 6 wk significantly inhibited the volume of HEC-1A tumors by 43%, tumor weight by 40% compared with controls and prolonged the tumor doubling time from 18.7 +/- 1.4 to 25.4 +/- 3.8 d. Administration of 20 mug MZ-J-7-118, sc, twice a day significantly (P < 0.05) decreased HEC-1A growth, as evidenced by a 57.9% decrease in tumor volume, a 50.7% reduction in tumor weight, and the extension of tumor doubling time from 17.5 +/- 2.8 to 36.4 +/- 6.5 d. Therapy with GHRH antagonists significantly decreased serum IGF-I levels in experiment 1, and significantly increased tumoral IGF-I levels in experiment 2 in treated mice. Levels of IGF-II and vascular endothelial growth factor-A in tumors were not changed. Specific high affinity binding sites for GHRH were found on HEC-1A tumor membranes using ligand competition assays with (125)I-labeled GHRH antagonist JV-1-42. MZ-J-7-118 displaced radiolabeled JV-1-42 with an IC(50) of 0.13 +/- 0.04 nm. The expression of mRNA for GHRH and splice variants of the GHRH receptor in HEC-1A tumors was demonstrated by real-time RT-PCR analysis. HEC-1A cells cultured in vitro secreted GHRH into the medium. The GHRH antagonist MZ-J-7-118 inhibited the growth of HEC-1A cells in vitro. Our results indicate that GHRH antagonists can reduce the growth of human endometrial cancer and could be used as an alternative adjuvant therapy for the management of endometrial cancer.
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PMID:Inhibition of growth of experimental human endometrial cancer by an antagonist of growth hormone-releasing hormone. 1578 1

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

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