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 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

The insulin-like growth factors (IGFs) I and II are present in extracellular fluids associated with specific binding proteins (IGFBPs) that can modify their biologic actions. These studies were undertaken to determine which forms of IGFBP are secreted by endometrial carcinoma (HEC-1B) and breast carcinoma (MDA-231) cells, to characterize variables that control IGFBP secretion, and to study the effect of IGFBP-1 and IGFBP-2 on IGF-I stimulated cell proliferation. Secreted IGFBPs were identified by ligand blotting and IGFBP-1 was quantified using a specific radioimmunoassay (RIA). MDA-231 cell conditioned media (CM) contained four (43,000, 39,000, 30,000 and 24,000 Mr) forms of IGFBP, and HEC-1B cell CM contained three forms (39,000, 34,000 and 30,000 Mr). Immunoblotting showed that the 30,000 Mr form secreted by both cell types was IGFBP-1. Likewise the 34,000 Mr band in HEC-1B media reacted with IGFBP-2 antiserum and the 39,000 and 43,000 Mr bands reacted with IGFBP-3 antiserum. IGF-I stimulated the secretion of IGFBP-3 from both cell types and IGFBP-2 from HEC-1B cells but either decreased or caused no change in secretion of IGFBP-1 and a 24,000 Mr form. In contrast, insulin inhibited the secretion of IGFBP-1 but increased the secretion of the 24,000 Mr form. Compounds that elevate intracellular cAMP levels increased the secretion of IGFBP-3, IGFBP-1, and the 24,000 Mr form from both MDA-231 and HEC-1B cells. When sparse cultures of MDA-231 cells were used, addition of IGF-I caused a 24% increase in cell number after 48 hr. This mitogenic response was enhanced by the presence of recombinant human IGFBP-1 (45% increase in cell number, P less than 0.001). Bovine IGFBP-2 did not potentiate IGF-I stimulated cell proliferation. These findings show that two tumor cell lines secrete distinct forms of IGFBPs and that there is differential regulation of IGFBP secretion. At least one form secreted by both tumors may act as a positive autocrine modulator of IGF-I's growth stimulating actions.
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PMID:Secretion and biological actions of insulin-like growth factor binding proteins in two human tumor-derived cell lines in vitro. 171 44

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

The present study was undertaken to determine whether endometrial cancer cell line HEC-1-A differ from nontransformed cells, in that the cAMP and protein kinase C pathways may enhance IGF-I effects in mitogenesis by acting at the G1 phase of the cell cycle instead of G0. Immunofluorescence staining of HEC-1-A cells using the proliferating cell nuclear antigen (PCNA) monoclonal antibody and flow cytometric analysis determined that HEC-1-A cells do not enter the G0 phase of the cell cycle when incubated in a serum-free medium. Approximately 51% of the cells were in G1, 12% were in S and 37% in G2 phase of the cell cycle prior to treatment. Forskolin and phorbol-12-myristate 13-acetate (PMA) were used to stimulate cAMP production and protein kinase C activity, respectively. IGF-I, forskolin and PMA each increased (P < 0.01) [3H]-thymidine incorporation in a dose and time dependent manner. The interaction of forskolin and PMA with IGF-I was then determined. Cells preincubated with forskolin or PMA followed by incubation with IFG-I incorporated significantly more (P < 0.01) [3H]-thymidine into DNA than controls or any treatment alone. It is concluded that forskolin and, to a lesser extent, PMA exert their effect at the G1 phase of the cycle to enhance IGF-I effects in cell proliferation.
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PMID:cAMP and PMA enhance the effects of IGF-I in the proliferation of endometrial adenocarcinoma cell line HEC-1-A by acting at the G1 phase of the cell cycle. 773 22

A plasminogen activator (PA) system is involved in ovulation, implantation, tumor invasion and metastasis. In order to clarify the regulation of this PA system in endometrial cells, we examined which agent affecting cellular function altered tissue-type plasminogen activator (t-PA) secretion by endometrial carcinoma cell line (KLE cells) in vitro. Triiodothyronine, retinoic acid, insulin, 8-bromo-cAMP, PDGF, IGF-I, basic FGF or TNF-alpha did not alter t-PA secretion while the activator of protein kinase C, phorbol myristate acetate (PMA) stimulated t-PA secretion in a dose-dependent fashion (10(-10)-10(-8) M). The time required to give a statistically significant increase in t-PA over control was 3 hours, and the maximal increase was seen after 24 hours of exposure. Another active phorbol ester, PDD also stimulated t-PA secretion while inactive forms of phorbol ester, 4 alpha-PDD and phorbol did not alter it. Cholera toxin or 8-bromo-cAMP did not affect t-PA secretion, but enhanced PMA-stimulated t-PA secretion. Cycloheximide and actinomycin D completely abolished PMA-stimulated t-PA secretion. These results suggest that (1) t-PA secretion in the endometrial carcinoma cell is modulated by a protein kinase C system, (2) This effect is through new RNA production and protein synthesis. (3) There is a complicated relationship between protein the kinase C and protein kinase A system as to the regulation of t-PA secretion. This would be a suitable model to clarify the PA system in endometrial cells.
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PMID:[Effect of phorbol ester on tissue-type plasminogen activator (t-PA) secretion in endometrial carcinoma cell line in vitro]. 812 84

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

A significant increase in endometrial cancer incidence in tamoxifen-treated breast cancer patients has been reported in many recent studies. The major growth stimulators of endometrial tumors are estrogens, but paradoxically, tamoxifen, a known antiestrogen, also stimulates their growth. The mode of action of estrogen can be partially explained by the modulation of insulin-like growth factor (IGF) autocrine or paracrine action. The purpose of the present study was to examine the involvement of the IGF system in the tamoxifen-stimulated growth of Ishikawa endometrial cancer cells by quantitating the IGF-I receptors and their phosphorylation, as well as membrane associated and secreted IGF-binding proteins (IGFBPs). Tamoxifen did not affect the number or affinity of IGF-I receptors. On the other hand, tamoxifen, similar to estradiol, increased IGF-I-stimulated tyrosine phosphorylation of cellular substrates. In contrast, in MCF-7 mammary cancer cells, tamoxifen reduced IGF-induced tyrosine phosphorylation in the presence of estradiol. The pure antiestrogen LY156758 did not affect Ishikawa basal cell growth but inhibited estradiol- and tamoxifen-induced growth. Growth inhibition by LY156758 of tamoxifen and estradiol-stimulated cells was accompanied by a corresponding inhibition of IGF-stimulated tyrosine phosphorylation. Tamoxifen caused a 3-fold decrease in membrane-associated IGFBPs. Moreover, a reduction in soluble IGFBPs was also observed, making the IGF peptides more available to the receptors. A parallel decrease in IGFBP-3 mRNA was also detected. These experiments suggest that tamoxifen, like estradiol, directly sensitizes endometrial cancer cells to the effects of IGFs that act through the type I receptor. Furthermore, the decrease in IGFBPs and the increase in tyrosine phosphorylation in the presence of tamoxifen provides a molecular mechanism that accounts for the uterotropic effects that are seen with tamoxifen therapy.
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PMID:Stimulation of endometrial cancer cell growth by tamoxifen is associated with increased insulin-like growth factor (IGF)-I induced tyrosine phosphorylation and reduction in IGF binding proteins. 860 78

The involvement of the IGF system in the growth regulation of hormone-dependent (e.g. endometrial and breast) cancer cells was studied. We chose two opposing effects of tamoxifen: the paradoxical stimulation of Ishikawa endometrial cancer cells growth and its inhibitory effect on MCF-7 mammary cancer cells. The results clearly confirm our working hypothesis that the IGF system is involved in growth regulation of these cancer cells irrespective of the direction of the drug effect. The following parameters of the IGFs system were studied: IGF-I receptors, IGF-I stimulated protein tyrosine phosphorylation, and membrane-associated and secreted IGF-binding proteins (IGFBPs). In Ishikawa cells, tamoxifen, similar to estradiol, increased IGF-I stimulated tyrosine phosphorylation of cellular substrates in accordance with its effect on cell growth. This effect of tamoxifen was inverted in MCF-7 cells. Tamoxifen did not affect the number or affinity of IGF-I receptors in both Ishikawa and MCF-7 cells, however, it caused a three-fold decrease in membrane-associated IGFBPs in the endometrial cells but an increase in these proteins in breast cancer cells. Similar but much less pronounced changes in soluble IGFBPs were observed. Our results indicate that the opposing growth effects of tamoxifen an endometrial and mammary cancer cells are associated with modulation of the IGF system components, mainly with reciprocal changes in membrane-associated IGFBPs.
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PMID:Components of the IGF system mediate the opposing effects of tamoxifen on endometrial and breast cancer cell growth. 881 96

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