leptin and Ovarian-Neoplasms

An increasing number of studies emphasize the role of inflammation and metabolic changes in the induction of cancer-related symptoms, which can affect cancer evolution and prognosis. These changes result from the interactions between the tumor and the host. To date, however, markers of this peculiar condition, which can help clinicians to manage patients better, have still not been identified with certainty. Epithelial ovarian cancer (EOC) appears to be particularly appropriate to study these interactions because of its biological characteristics, its peculiar evolution, and the relevant scientific evidence available. Immunosuppression, anemia, depression, and weight loss affect the evolution of EOC and appear to be directly related to the immune-metabolic changes. In light of the aforementioned evidence, our review will focus on interleukin-6 (IL-6) and its role as potential marker of the patients' immune-metabolic status, to better monitor disease outcome and identify the most appropriate therapeutic strategy in EOC. Furthermore, leptin will be discussed as a sensor of the changes of energy metabolism induced by IL-6.

Topics: Anemia; Biomarkers; Carcinoma, Ovarian Epithelial; Endocrine System; Energy Metabolism; Female; Humans; Immune System; Interleukin-6; Leptin; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis

BRCA1 and BRCA2 mutation carriers have an 18%-60% and 11%-27% lifetime risk of developing ovarian carcinoma, respectively. Prophylactic bilateral salpingo-oophorectomy reduces the risk of this malignancy by up to 96%. Gynecological screening programs with periodical trans-vaginal ultrasound and serum CA125 assay have been widely used in women at hereditary high risk of ovarian carcinoma, but clinical results have been conflicting. These surveillance protocols have often fallen short of expectations because of the advanced stage of ovarian carcinoma in the identified screened women. Several investigations have been addressed to the detection of additional tumor markers able to generate more reliable screening tools. The combined serum assay of leptin, prolactin, osteopontin, CA125, macrophage inhibiting factor and insulin-like growth factor-II appears to have a significant better diagnostic reliability compared with serum CA125 alone in discriminating healthy individuals from ovarian carcinoma patients, and therefore, it could have a role in the screening of women at high risk for this malignancy. As far as chemoprevention is concerned, oral contraceptives significantly reduce the ovarian carcinoma risk also in BRCA mutation carriers, whereas the efficacy of fenretinide is still under investigation.

Topics: Biomarkers, Tumor; BRCA1 Protein; BRCA2 Protein; CA-125 Antigen; Female; Humans; Insulin-Like Growth Factor II; Leptin; Macrophage Migration-Inhibitory Factors; Membrane Proteins; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Osteopontin; Ovarian Neoplasms; Ovariectomy; Prolactin; Ultrasonography

In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer.. This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided.. Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99).. Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.

Topics: Biomarkers; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Female; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Ovarian Neoplasms

Obesity is associated with increased mortality among ovarian cancer and is a poor prognostic factor. There are significant links between the leptin hormone, a product of the obesity gene, and the development of ovarian cancer. Leptin is a vital hormone-like cytokine secreted from adipose tissue and is mainly involved in the maintenance of energy homeostasis. It regulates several intracellular signaling pathways and also interacts with various hormones and energy regulators. It acts as a growth factor by stimulating cell proliferation and differentiation and in this way contributes to cancer cell development. The aim of the study was to investigate the effects of leptin on human ovarian cancer cells.. In this study, the effects of increasing the concentration of leptin were investigated on the cell viability of OVCAR-3 and MDAH-2774 ovarian cancer lines by MTT assay. Moreover, to elucidate the molecular mechanisms of leptin in ovarian cancer cells, changes in the expression levels of 80 cytokines were evaluated after leptin treatment. Leptin increases the proliferation of both ovarian cancer cell lines. IL-1 level was increased in OVCAR-3 cells and TGF-β level was increased in MDAH-2774 cells after leptin treatment. A decrease in IL-2, MCP-2/CCL8 and MCP-3/CCL7 levels was detected in both ovarian cancer cell lines with leptin administration. An increase in IL-3 and IL-10 expressions, insulin-like growth factor binding proteins (IGFBP) IGFBP-1, IGFBP-2 and IGFBP-3 levels were detected in both ovarian cancer cell lines with leptin administration. In conclusion; leptin has a proliferative effect on human ovarian cancer cell lines and affects different cytokines in different types of ovarian cancer cells.

Topics: Apoptosis; Cell Line, Tumor; Cytokines; Female; Humans; Leptin; Obesity; Ovarian Neoplasms

Ovarian cancer is one of the most serious problems in modern oncological gynecology. The link between obesity (expressed in BMI, WHR, waist circumference, body weight) and ovarian cancer has been poorly studied. Obesity is defined as an excessive accumulation of bodily fat, exceeding its physiological needs and adaptability. Study results suggest a link between specific histological types of ovarian cancer with increased patients' BMI. Adipose tissue is hormonally active and secretes biologically active proteins called adipokines. Resistin and leptin may show proliferative and anti-apoptotic effects. There is currently increasing attention to adipokine levels in ovarian cancer research. The influence of adiponectin on the secretion of angiogenic factors by ovarian cancer cells has been shown. It has been proven that leptin is associated with a worse prognosis for patients treated with platinum compounds combined with paclitaxel/docetaxel. The relation has been observed between the level of resistin and the growth of neoplastic cells, their spread and the resistance to chemotherapy. The level of AdipoR1 may be independent prognostic factor in the case of epithelial ovarian cancer. The role of adipokine in the neoplasm development requires further investigation, in the view of fact that results of current research are still inconclusive. Considering increasing number of people suffering from obesity as well as the current analysis results, it is necessary to extend experimentation on the influence of obesity on the development and prognosis of ovarian cancer.

Topics: Adipokines; Carcinoma, Ovarian Epithelial; Female; Humans; Leptin; Obesity; Ovarian Neoplasms; Prognosis; Resistin

Trial on five plasma biomarkers (CA125, HE4, OPN, leptin, prolactin) and their possible role in differentiating benign from malignant ovarian tumors.. In this unicentric prospective trial preoperative blood samples of 43 women with ovarian masses determined for ovarian surgery were analyzed. 25 patients had pathologically confirmed benign, 18 malignant ovarian tumors. Blood plasma was analyzed for CA125, HE4, OPN, leptin, prolactin and MIF by multiplex immunoassay analysis. Each single protein and a logistical regression model including all the listed proteins were tested as preoperative predictive marker for suspect ovarian masses.. Plasma CA125 was confirmed as a highly accurate tumor marker in ovarian cancer. HE4, OPN, leptin and prolactin plasma levels differed significantly between benign and malignant ovarian masses. With a logistical regression model a formula including CA125, HE4, OPN, leptin and prolactin was developed to predict malignant ovarian tumors. With a discriminatory AUC of 0.96 it showed to be a highly sensitive and specific diagnostic test for a malignant ovarian tumor.. The calculated formula with the combination of CA125, HE4, OPN, leptin and prolactin plasma levels surpasses each single marker in its diagnostic value to discriminate between benign and malignant ovarian tumors. The formula, applied to our patient population was highly accurate but should be validated in a larger cohort.. Clinical Trials.gov under NCT01763125 , registered Jan. 8, 2013.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Biomarkers, Tumor; CA-125 Antigen; Carcinoma, Ovarian Epithelial; Early Detection of Cancer; Female; Humans; Leptin; Logistic Models; Middle Aged; Osteopontin; Ovarian Neoplasms; Prolactin; Prospective Studies; WAP Four-Disulfide Core Domain Protein 2; Young Adult

Topics: Adipokines; Adiponectin; Body Mass Index; Carcinoma, Renal Cell; Colorectal Neoplasms; Correlation of Data; Endometrial Neoplasms; Female; Genome-Wide Association Study; Humans; Leptin; Mendelian Randomization Analysis; Obesity; Ovarian Neoplasms; Pancreatic Neoplasms; Plasminogen Activator Inhibitor 1; Principal Component Analysis; Receptors, Leptin; Risk Factors

Ovarian cancer is most frequently detected in the advanced stage. Although its pathogenesis is not fully elucidated, it is assumed that body susceptibility and hormonal disorders are responsible. The role of some cytokines as predictors in the treatment process is still investigated. The aim of the study was to determine the relationship of adiponectin and leptin with the disease severity and response to chemotherapy.. Forty-three ovarian cancer patients were treated by systemic treatment. Patients received 5-7 cycles of chemotherapy - paclitaxel/carboplatin with or without bevacizumab. Using standard ELISA kits before and after chemotherapy, adiponectin and leptin concentrations were determined in the blood serum.. The average adiponectin concentration before chemotherapy was found to be 8.83 ± 3.19 μg/ml, as compared to 10.37 ± 4.18 μg/ml (increase by 17.44%, p < 0.001) after treatment. Mean pre-treatment leptin concentration was 16.89 ± 15.54 ng/ml, and 21.77 ± 14.69 ng/ml after chemotherapy (increase by 28.89%, p < 0.01). A positive correlation was found between leptin concentration and age and BMI. There was no relationship of the disease severity with the response to treatment and the concentration of the adipokines. The leptin/adiponectin ratio (L/A) before treatment correlated with better response to chemotherapy.. Adiponectin and leptin did not correlate with the stage of ovarian cancer and response to chemotherapy. The L/A ratio may be considered a predictor of clinical response to treatment.

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Carboplatin; Female; Humans; Leptin; Middle Aged; Ovarian Neoplasms; Paclitaxel; Treatment Outcome

Leptin induces ovarian cancer cell invasion via overexpression of MMP7, MMP9, and upA. In addition, the key role of ERα in leptin-increased cell growth was indicated. However, the influence of ER on leptin-mediated cell invasion remains still unknown. The present study was designed to evaluate the E2-independent effect of ERα/β on leptin-mediated cell invasion and cell proliferation in ovarian cancer. We utilized SKOV3 cancer (expressing OB-Rb and ERα/β, insensitive to estrogen) and OVCAR3 (expressing OB-Rb) cell lines to show the involvement of ER in leptin-mediated effects in an E2-independent manner. MTT, BrdU, and BD matrigel invasion assays were applied to analyze cell growth, proliferation, and invasion. The siRNA approach was used to confirm the role of ERα/β in leptin effects. Moreover, western blotting and Real-time PCR were employed to detect the OB-Rb, ER, MMP9/7, and upA proteins and mRNAs. Leptin, in the absence of E2, increased ERα expression in SKOV3 cells, which was attenuated using knockdown of OB-Rb gene by siRNA. The effect of leptin on the cell growth was promoted in the presence of PPT, but not in the presence of DNP and E2, which was lost when OB-Rb siRNA was transfected. Furthermore, ERα gene silencing and/or pre-incubation with ER antagonist (ICI 182,780, 10 nM) significantly reduced cell invasion and MMP9 expression stimulated by leptin. In conclusion, our findings demonstrated that ERα, but not ERβ, is involved in leptin-induced ovarian cancer in an E2-independent manner, providing new evidence for cancer progression in obesity-associated ovarian cancer.

Topics: Carcinoma, Ovarian Epithelial; Estrogen Receptor alpha; Female; Humans; Leptin; Neoplasm Proteins; Ovarian Neoplasms; Receptors, Leptin

Leptin, an adipokine secreted by adipose tissue, induces cell invasion and metastasis. MMP7 is a member of the matrix metalloproteinase family that plays an important role in cell invasion. Here we evaluate the possible role and underlying mechanism of MMP7 in the leptin-mediated cell invasion in ovarian cancer cell lines. All experiments were carried out in cultured SKOV3, OVCAR3, and CaoV-3 ovarian cell lines. MMP7 expression was determined using the Western blot following treatment to various concentrations of leptin for defined time intervals. The activation of ERK, JNK, and P38 MAP kinases were determined using Western blotting. Wound healing and BD matrigel invasion assays were used to measure cell migration and invasion. The siRNA approach and pharmacological inhibitors of ERK and JNK pathway were used to confirm the receptor-dependent effect of leptin and a role for ERK and JNK pathway. Zymography assay was employed to determine MMP2 and MMP9 activation. Results show that leptin induces ERK1/2 and JNK1/2 activation and subsequently promotes MMP7 expression in SKOV3 (4.8 ± 0.14 fold of control, P < 0.01) and OVCAR3 (3.1 ± 0.19 fold of control, P < 0.01) ovarian cancer cell lines. These effects was reversed by knockdown of OB-Rb and/or pre-incubation with PD98059 (ERK1/2 inhibitor), SP600125 (JNK1/2 inhibitor). Gelatin zymography showed that MMP7 gene silencing attenuated leptin-induced MMP9 activation in SKOV3 cell line. Taken together, our results suggest new evidences for a modulatory effect of leptin in regulation of ovarian cancer cell invasion by stimulating MMP7 expression via ERK and JNK pathways.

Topics: Anthracenes; Cell Line, Tumor; Cell Movement; Female; Flavonoids; Gene Knockdown Techniques; Humans; Leptin; MAP Kinase Signaling System; Matrix Metalloproteinase 7; Neoplasm Invasiveness; Ovarian Neoplasms

Obesity and its comorbidities constitute a serious health burden worldwide. Leptin plays an important role in diet control; however, it has a stimulatory potential on cancer cell proliferation. The OB3 peptide, a synthetic peptide, was shown to be more active than leptin in regulating metabolism but with no mitogenic effects in cancer cells.. In this study, we investigated the proliferative effects, gene expressions and signaling pathways modulated by leptin and OB3 in human ovarian cancer cells. In addition, an animal study was performed.. Leptin, but not OB3, induced the proliferation of ovarian cancer cells. Interestingly, OB3 blocked the leptin-induced proliferative effect when it was co-applied with leptin. Both leptin and OB3 activated the phosphatidylinositol-3-kinase (PI3K) signal transduction pathway. In addition, leptin stimulated the phosphorylation of signal transducer and activator of transcription-3 (STAT3) Tyr-705 as well as estrogen receptor (ER)α, and the expression of ERα-responsive genes. Interestingly, all leptin-induced signal activation and gene expressions were blocked by the co-incubation with OB3 and the inhibition of extracellular signal-regulated kinase (ERK)1/2. Coincidently, leptin, but not OB3, increased circulating levels of follicle-stimulating hormone (FSH) which is known to play important roles in the initiation and proliferation of ovarian cancer cells.. In summary, our findings suggest that the OB3 peptide may prevent leptin-induced ovarian cancer initiation and progression by disrupting leptin-induced proliferative signals via STAT3 phosphorylation and ERα activation. Therefore, the OB3 peptide is a potential anticancer agent that might be employed to prevent leptin-induced cancers in obese people.

Topics: Animals; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Peptide Fragments; Signal Transduction

There are no data showing a direct correlation between obesity and increased blood leptin levels with folliculoma. Moreover, folliculoma is not the best studied among other ovarian cancer types. We investigated whether oestradiol can modulate ObR expression in some oestrogen-responsive tissues and that leptin exerts its activity not only via the leptin receptor but also through cross talk with other signalling systems. We hypothesise that blocking ObR expression could be a novel treatment for gonadal ovarian cancer.. We evaluated the effect of SHLA, Lan1 and Lan2 blockers on cell proliferation (BrdU incorporation assay), ObR and ERα/β gene expression (qPCR), oestradiol secretion (ELISA) and cell cycle protein expression (Western blot) in the non-cancerous cell line HGrC1 and two granulosa cancer cell lines: the juvenile form (COV434) and the adult form (KGN).. ObR gene expression in cancer cell lines was 50% higher than in the non-cancer cells. Lan-1 and Lan-2 decreased ObR expression in COV434, while it had no effect in KGN cells. Higher ERβ expression in non-cancer and higher ERα expression in both cancer cell lines was noted. SHLA and Lan-1 changed the ratio towards greater expression of ERβ, characteristic of non-cancer granulosa cells. All ObR antagonists in HCrC1 and KGN but only Lan-2 in COV434 reversed leptin-stimulated proliferation. In both non-cancer and cancer granulosa cells, leptin acts as a cyclinD/cdk4, cyclin A/cdk2 and E2F inhibitor.. These results indicate that SHLA and Lan2 are promising leptin receptor inhibitors that can eliminate the negative effects of leptin. These compounds should be considered in further ex vivo studies on the cancer microenvironment.

Topics: Blotting, Western; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Granulosa Cell Tumor; Humans; Leptin; Obesity; Ovarian Neoplasms; Receptor Cross-Talk; Receptors, Leptin

Screening for ovarian cancer (OC) in women at high risk consists of a combination of carbohydrate antigen 125 (CA125) and transvaginal ultrasound, despite their low sensitivity and specificity. This could be improved by the combination of several biomarkers, which has been shown in average risk patients but has not been investigated until now in female BRCA mutation carriers.. Using a multiplex, bead-based, immunoassay system, we analyzed the concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, CA125 and human epididymis antigen 4 in 26 healthy wild type women, 26 healthy BRCA1 mutation carriers, 28 wildtype OC patients and 26 OC patients with BRCA1 mutation.. Using the ROC analysis, we found a high overall sensitivity of 94.3% in differentiating healthy controls from OC patients with comparable results in the wildtype subgroup (sensitivity 92.8%, AUC = 0.988; p = 5.2e-14) as well as in BRCA1 mutation carriers (sensitivity 95.2%, AUC = 0.978; p = 1.7e-15) at an overall specificity of 92.3%. The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065).. We have developed an algorithm, which can differentiate between healthy women and OC patients and have for the first time shown, that such an algorithm can also be used in BRCA mutation carriers. To clarify a suggested benefit to the existing early detection program, large prospective trials with mainly early stage OC cases are warranted.

Topics: Adult; Aged; Biomarkers, Tumor; BRCA1 Protein; CA-125 Antigen; Early Detection of Cancer; Female; Humans; Insulin-Like Growth Factor II; Leptin; Middle Aged; Mutation; Osteopontin; Ovarian Neoplasms; Prolactin

Epithelial ovarian cancer (OC) is the leading cause of death in patients with gynecologic malignancy. Malignant ascites, a shared symptom of advanced OC patients, plays an important role in the peritoneal metastasis cascade of OC. Since leptin existed in great amount in malignant ascites, we speculated that it might be involved in the modulation of tumor cells malignant behavior.. Here, we demonstrated that blocking of leptin could significantly suppress ovarian malignant ascitesinduced metastatic aggravation of OC cells. Furthermore, our results suggested that leptin was highly expressed in OC and correlated with poor outcome of OC patients. Recombinant leptin notably promoted the migration, invasion and proliferation of OC cells.. Mechanistically, we found that leptin induced epithelial-mesenchymal transition (EMT) program in OC cells through the activation of the PI3K/Akt/mTOR pathway. Pharmacological inhibition of the PI3K/Akt/mTOR pathway partly impaired leptin-induced malignant transformation of OC cells. More importantly, our in vivo xenograft experiment showed that blocking of leptin could dramatically inhibit OC cells peritoneal dissemination.. Collectively, this study emphasized the importance of leptin in OC progression and illustrated a novel mechanism that the PI3K/Akt/mTOR pathway was involved in leptin-induced EMT. Our findings provide new insights into leptin exertion on OC metastasis and identify the potential of leptin neutralizing as a novel strategy against OC peritoneal dissemination.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

Previous studies have shown that leptin, an adipocyte-secreted hormone, stimulates ovarian cancer invasion. Here, we investigated the contribution of uPA in leptin-induced ovarian cancer cell invasion. The cell invasion and migration experiments were carried out using matrigel invasion and wound healing assays in ovarian cancer cell lines (OVCAR3, SKOV3and CaoV-3). The mechanism underlying the invasive effect of leptin was examined using cell transfection with Ob-Rb siRNA, pre-treatment with a specific inhibitor of RhoA and ROCK, RhoA activation assay, OB-Rb, Rock and upA protein expression. Our results show that leptin induced ovarian cancer cell invasion via up-regulating upA in a time and dose-dependent manner, which was attenuated using knockdown of OB-Rb by siRNA. Moreover, pre-incubation with C3 (inhibitor of RhoA) and Y-27632 (inhibitor of ROCK) effectively attenuated leptin-induced upA expression and inhibited invasive ability of ovarian cancer cells. We also found that pretreatment with inhibitors of PI3K/AKT (LY294002), JAK/STAT (AG490) and NF-kB (BAY 11-7082) significantly reduced leptin-induced upA expression. Collectively, our findings demonstrate that OB-Rb, RhoA/ROCK, PI3K/AKT, JAK/STAT pathways and NF-kB activation are involved in leptin-induced upA expression. These results may provide a new mechanism that facilitates leptin-induced ovarian cancer invasion.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Silencing; Humans; Leptin; Neoplasm Invasiveness; NF-kappa B; Ovarian Neoplasms; Phosphorylation; Receptors, Leptin; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Urokinase-Type Plasminogen Activator

A number of leptin receptor antagonists have been synthesised for therapeutic use, with pre-clinical tests suggesting their future use in anticancer therapy. To our knowledge, there are no data concerning the possible application of leptin receptor blockers in ovarian cancer.. In this study, we evaluated two leptin receptor antagonists: superactive human leptin antagonist (SHLA) and quadruple leptin mutein, Lan-2 (L39A/D40A/F41A/I42A), on cell proliferation (Alamar Blue test, BrdU assay), cell cycle gene (qPCR) and protein expression (Western blot) and cell signalling pathways (Western blot) in three different types of cell lines: OVCAR-3, CaOV-3 and HOSEpiC.. Both receptor blockers had no effect on non-cancerous HOSEpiC cell line proliferation; however, both reversed the stimulatory effect of leptin on CaOV-3 cell line proliferation to control levels and to below control levels in OVCAR-3 cells. In metastatic carcinoma CaOV-3, both ObR antagonists had an inhibitory effect on the cdk2/cyclin D1 complex, while in serous carcinoma, OVCAR-3, they only had an effect on cdk2 and cdk4 protein expression. SHLA had an inhibitory effect on all investigated signalling pathways in OVCAR-3, while only on Stat3 in CaOV-3. Lan-2 had an inhibitory effect on Stat3 and ERK1/2 in CaOV-3, while in OVCAR-3 it only affected Akt protein phosphorylation.. Based on these results, we conclude that SHLA and Lan-2 are promising leptin receptor inhibitors which could be used to block leptin activity, eliminating its negative effects on activities related to carcinogenesis. However, the selection of a specific antagonist should be related to tumour type.

Topics: Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Cell Line; Cell Line, Tumor; Cell Proliferation; Female; Humans; Leptin; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

CA-125 protein is used as a marker in clinical practice for the diagnosis of endometriomas. The aim of this study was to determine whether endometriomas are accompanied by an increased level of urocortin, ghrelin, and leptin, as well as the increased parameters of blood cell count, fibrinogen, and CA-125.. The study included 86 women aged 18-38 years who had been treated laparoscopically for lesions in the adnexa with the characteristics of endometriomas and mature teratoma, during the period September 2009 to November 2012. The statistical analysis was performed using the nonparametric Mann-Whitney U test and the Spearman rank correlation coefficients (p ≤ 0.05).. The medians were 105.31 pg/mL versus 120.84 pg/mL for urocortin, 7.16 pg/mL versus 9.13 pg/mL for leptin and 584.33 pg/mL versus 657.82 pg/mL for ghrelin (p > 0.05), respectively. Analyzing the parameters of blood cell count, statistically significant differences were shown in the respective groups for leucocyte level (5.35 × 10(9)/L vs. 6.7 × 10(9)/L; p = 0.029), fibrinogen level (3.12 mg% vs. 2.57 mg%; p = 0.001), and CA-125 (36.50 U/mL vs. 15.08 U/mL; p = 0.001).. In conclusion, the prognostic values for CA-125, leukocytes, and fibrinogen may prove a very useful tool for the diagnosis of lesions in the adnexa of the type endometriomas.

Topics: Adolescent; Adult; Biomarkers; CA-125 Antigen; Endometriosis; Female; Fibrinogen; Ghrelin; Humans; Leptin; Leukocyte Count; Ovarian Neoplasms; Sensitivity and Specificity; Teratoma; Urocortins; Young Adult

The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin's effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women.

Topics: Aged; Ascites; Cell Line, Tumor; Cell Movement; Cohort Studies; Disease Progression; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Genome, Human; Humans; Leptin; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplastic Stem Cells; Obesity; Ovarian Neoplasms; Overweight; Prognosis; Recombinant Proteins; Recurrence; Treatment Outcome

Obesity is a pandemic and major risk factor for cancers. The reduction of obesity would have been an effective strategy for cancer prevention, but the reality is that worldwide obesity has kept increasing for decades, remaining a major avoidable cancer risk secondary only to smoke. The present studies suggest that vitamin D may be an effective agent to reduce obesity-associated cancer risks in women. Molecular analyses showed that leptin increased human telomerase reverse transcriptase (hTERT) mRNA expression and cell growth through estrogen receptor-α (ERα) activation in ovarian cancer cells, which was suppressed by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The suppression was compromised when miR-498 induction by the hormone was depleted with microRNA (miRNA) sponges. In mice, high-fat diet (HFD) stimulation of ovarian tumor growth was remarkably suppressed by 1,25(OH)2D3 analogue EB1089, which was also compromised by miR-498 sponges. EB1089 did not alter HFD-induced increase in serum leptin levels but increased miR-498 and decreased the diet-induced hTERT expression in tumors. Quantitative RT-PCR analyses revealed an inverse correlation between hTERT mRNA and miR-498 in response to 1,25(OH)2D3 in estrogen-sensitive ovarian, endometrial, and breast cancers. The studies suggest that miR-498-mediated hTERT downregulation is a key event mediating the anti-leptin activity of 1,25(OH)2D3 in estrogen-sensitive tumors in women.

Topics: Animals; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Proliferation; Diet, High-Fat; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mice; MicroRNAs; Ovarian Neoplasms; Telomerase; Vitamin D

Obesity impacts outcome in women with epithelial ovarian cancer (EOC), although its exact role and the molecular mechanisms remain poorly defined. Adipocytes secrete leptin and adiponectin, and the leptin to adiponectin (L:A) ratio is correlated with poor survival in other malignancies. We hypothesized that the L:A ratio is associated with survival in women with EOC.. We queried the institutional tumor registry for patients with advanced stage EOC and identified a cohort of 161 women with banked fasting prediagnostic serum samples. Patients underwent cytoredutive surgery followed by platinum-based chemotherapy. Sera were assayed for leptin and adiponectin, and clinico-pathologic data were abstracted. Standard statistical tests were performed.. 161 patients met inclusion criteria. We identified a significant correlation between BMI and leptin and the L:A ratio, but not adiponectin, in this cohort (r=0.46, 0.46, and -0.13, respectively; p=0.001, 0.001, and 0.106). Women with low L:A ratios demonstrated statistically longer disease-specific survival (57 months) compared to those with median or high levels (49 and 37 months, respectively; p=0.02). On multivariate analysis, we determined that BMI and age, but not L:A ratio, retained significance as independent prognostic factors for survival (p=0.04, 0.004, and 0.895, respectively).. In this cohort, the L:A ratio correlated statistically with clinical outcome, but did not independently predict survival. Obesity remains a modifiable risk factor in women with EOC. Further studies are needed to determine if leptin and/or adiponectin may be potential therapeutic targets in obese women with EOC.

Topics: Adiponectin; Adult; Aged; Biomarkers; Body Mass Index; Carcinoma, Ovarian Epithelial; Combined Modality Therapy; Female; Humans; Leptin; Middle Aged; Multivariate Analysis; Neoplasms, Glandular and Epithelial; Obesity; Ovarian Neoplasms; Prognosis; Registries; Retrospective Studies; Survival Analysis

The immune system is a key player in fighting cancer. Thus, we sought to identify a molecular 'immune response signature' indicating the presence of epithelial ovarian cancer (EOC) and to combine this with a serum protein biomarker panel to increase the specificity and sensitivity for earlier detection of EOC.. Comparing the expression of 32,000 genes in a leukocytes fraction from 44 EOC patients and 19 controls, three uncorrelated shrunken centroid models were selected, comprised of 7, 14, and 6 genes. A second selection step using RT-qPCR data and significance analysis of microarrays yielded 13 genes (AP2A1, B4GALT1, C1orf63, CCR2, CFP, DIS3, NEAT1, NOXA1, OSM, PAPOLG, PRIC285, ZNF419, and BC037918) which were finally used in 343 samples (90 healthy, six cystadenoma, eight low malignant potential tumor, 19 FIGO I/II, and 220 FIGO III/IV EOC patients). Using new 65 controls and 224 EOC patients (thereof 14 FIGO I/II) the abundances of six plasma proteins (MIF, prolactin, CA125, leptin, osteopondin, and IGF2) was determined and used in combination with the expression values from the 13 genes for diagnosis of EOC.. Combined diagnostic models using either each five gene expression and plasma protein abundance values or 13 gene expression and six plasma protein abundance values can discriminate controls from patients with EOC with Receiver Operator Characteristics Area Under the Curve values of 0.998 and bootstrap .632+ validated classification errors of 3.1% and 2.8%, respectively. The sensitivities were 97.8% and 95.6%, respectively, at a set specificity of 99.6%.. The combination of gene expression and plasma protein based blood derived biomarkers in one diagnostic model increases the sensitivity and the specificity significantly. Such a diagnostic test may allow earlier diagnosis of epithelial ovarian cancer.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Area Under Curve; Biomarkers, Tumor; Blood Proteins; CA-125 Antigen; Carcinoma, Ovarian Epithelial; Case-Control Studies; Cystadenoma; Female; Gene Expression Profiling; Humans; Insulin-Like Growth Factor II; Intramolecular Oxidoreductases; Leptin; Macrophage Migration-Inhibitory Factors; Membrane Proteins; Middle Aged; Neoplasms, Glandular and Epithelial; Oligonucleotide Array Sequence Analysis; Osteopontin; Ovarian Neoplasms; Prolactin; Retrospective Studies; ROC Curve; Young Adult

This study was designed to investigate the effect of bisphenol A and leptin on caspase-3 expression and activity in OVCAR-3 ovarian cancer cells. Caspase-3 and survivin expression was measured at the transcript level by real-time PCR and at the protein level by Western blotting. In addition, caspase-3 activity was measured, using a fluorometric assay, upon exposure to bisphenol A (40 nM) alone, leptin (2.5 nM) alone, and the combination of both agents. 17β-estradiol (40 nM) was used as a positive control for estrogenic properties of bisphenol A. Results showed that the interaction between bisphenol A and leptin, which was similar to that observed between 17β-estradiol and leptin, led to the inhibition of caspase-3 expression and activity in OVCAR-3 cells. Surprisingly, survivin was found to not be involved in the anti-apoptotic activity of either agent. Also, results showed that leptin inhibits caspase-3 activity by acting on the signal transducers and activators of transcription 3 (STAT3) pathway, but bisphenol A and 17β-estradiol by the extracellular-signal-regulated kinases 1/2 (ERK1/2) pathway. In conclusion, the study reveals that bisphenol A and leptin interact to inhibit caspase-3 expression and activity by modulating STAT3 and ERK1/2 signaling pathways in OVCAR-3 cells.

Topics: Benzhydryl Compounds; Caspase 3; Caspase Inhibitors; Cell Line, Tumor; Estradiol; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Inhibitor of Apoptosis Proteins; Janus Kinases; Leptin; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Ovarian Neoplasms; Phenols; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor; Survivin

The OVCAR-3 cell line expressing the long (ObRb) and short (ObRt) isoforms of leptin receptor mRNA was used to analyze the effect of leptin on the expression of selected genes and proteins involved in the cell cycle and apoptosis. OVCAR-3 cells were exposed to 2, 20, 40, and 100 ng/ml of leptin. Cell proliferation was determined using the alamarBlue cell viability test and flow cytometry. Apoptosis was measured using a cellular DNA fragmentation ELISA kit. The expression of selected cell cycle and apoptosis genes was evaluated by real-time PCR and confirmed by western blot. The stimulatory action of leptin on cell proliferation was observed as an increase in cells in the S and G2/M phases. Up-regulation of genes responsible for inducing cell proliferation and suppression of genes responsible for inhibition of proliferation were noted. Western blots revealed increased expression of cyclins D and A and inhibition of p21WAF1/CIP1 protein expression by leptin. Inhibition of DNA fragmentation was observed under all leptin doses. Suppression of genes involved in the extrinsic and intrinsic apoptotic pathway was observed. Western blots illustrated decreased Bad, TNFR1, and caspase 6 protein expression in response to leptin treatment. Leptin promotes ovarian cancer cell line growth by up-regulating genes and proteins responsible for inducing cell proliferation as well as down-regulating pro-apoptotic genes and proteins in apoptotic pathways. Results of this study warrant examining the relationship between the risk of ovarian cancer and elevated leptin levels in obese women.

Topics: Apoptosis; bcl-Associated Death Protein; Caspase 6; Cell Cycle; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; DNA Fragmentation; Female; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Leptin; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Receptors, Tumor Necrosis Factor, Type I; Up-Regulation

Leptin overexpression contributes to the tumorigenesis of ovarian cancer. However, the functional mechanism and effects remain unclear. The aberrant expression of tumor-related microRNAs may play an important role in the development of cancer. In this report, we demonstrate that crosstalk between leptin and microRNA-182 and microRNA-96 affects the transformation and proliferation of ovarian cancer cells. Our results showed that leptin enhanced the colony formation of ovarian cancer cells in soft agar. A water-soluble tetrazolium salts assay revealed that leptin promoted ovarian cancer cell (SKOV3 and A2780 cells) proliferation in a time- and dose-dependent manner. The growth effects of leptin on ovarian cancer cells were mediated via the reduced expression of forkhead box O3 and its downstream targets p27 and Bim. We demonstrated that leptin upregulated miRNAs that target forkhead box O3 via luciferase reporter assay. Further examination indicated that only the inhibition of microRNA-182 and/or microRNA-96 rescued the expression of forkhead box O3 inhibited by leptin, and their mimics promoted the proliferation of ovarian cancer cells. Moreover, the signal transducer and activator of transcription 5 pathway, but not the signal transducer and activator of transcription 3 pathway, was implicated in the leptin-mediated expression of microRNA-182 and microRNA-96. In conclusion, our findings suggest that the upregulation of microRNA-182 and microRNA-96 targeting forkhead box O3 plays a significant role in the pro-proliferation effect of leptin on ovarian cancer cells, which might provide preliminary experimental clues for the development of new therapies against ovarian cancer.

Topics: Cell Proliferation; Female; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Leptin; MicroRNAs; Ovarian Neoplasms; Signal Transduction; STAT5 Transcription Factor; Up-Regulation

Obesity is known to be an important risk factor for many types of cancer, such as breast, prostate, liver and endometrial cancer. Recently, epidemiological studies have indicated that obesity correlates with an increased risk of developing ovarian cancer, the most lethal gynecological cancer in developed countries. Leptin is predominantly produced by adipocytes and acts as a growth factor and serum leptin levels positively correlate with the amount of body fat. In this study, we investigated the effects of leptin on the growth of ovarian cancer cells and the underlying mechanism(s) of action. Our results showed that leptin stimulated the growth of the OVCAR-3 ovarian cancer cell line using MTT assay and trypan blue exclusion. Using western blot analysis, we found that leptin enhanced the expression of cyclin D1 and Mcl-1, which are important regulators of cell proliferation and the inhibition of apoptosis. To investigate the signaling pathways that mediate the effects of leptin, cells were treated with leptin plus specific inhibitors of JAK2, PI3K/Akt and MEK/ERK1/2 and analysis of the phosphorylation state of proteins was carried out by western blot assays. We showed that the activation of the MEK/ERK1/2 and PI3K/Akt signaling pathways were involved in the growth-stimulating effect of leptin on ovarian cancer cell growth and the specific inhibitors of PI3K/Akt and MEK/ERK1/2 revealed that these two pathways interacted with each other. Our data demonstrate that leptin upregulates the expression of cyclin D1 and Mcl-1 to stimulate cell growth by activating the PI3K/Akt and MEK/ERK1/2 pathways in ovarian cancer.

Topics: Apoptosis; Butadienes; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Flavonoids; Humans; Janus Kinase 2; Leptin; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Myeloid Cell Leukemia Sequence 1 Protein; Nitriles; Obesity; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Tyrphostins

We previously demonstrated that bisphenol A (BPA) promotes proliferation in OVCAR-3 human ovarian cancer cells. This study was designed to investigate the effects of BPA on leptin expression and activity in ovarian cancer. Real-time PCR, Western blot analysis and ELISA assays were used to quantify leptin receptor expression and leptin gene and protein expression after treatment with BPA at doses of 0.2, 2, 8 and 20ng/ml. Our data reveal leptin receptor expression but an absence of leptin gene and protein expression in OVCAR-3 cells. At doses of 8 and 20ng/ml, BPA had stimulatory effects on leptin receptor gene and protein expression. Leptin and BPA alone stimulated cell proliferation but BPA did not potentiate leptin activity. Similarly to leptin, but with different kinetics and duration, BPA induced phosphorylation of Stat3, ERK1/2 and Akt. In co-treatment experiments, the timing of protein phosphorylation represented an additive effect of BPA and leptin treatment. In conclusion, taking into consideration limitation of in vitro study, whether BPA by creating more binding sites for leptin and extending the time of leptin-induced Stat3, ERK1/2 and Akt phosphorylation, can potentiated leptin action in cancer cells, require confirmation by in vivo study.

Topics: Benzhydryl Compounds; Binding Sites; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Janus Kinases; Leptin; MAP Kinase Signaling System; Ovarian Neoplasms; Phenols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT Transcription Factors

To investigate biomarkers and clinical parameters to distinguish ovarian cancers from benign ovarian tumours.. Serum biomarkers (CA 125, human epididymis protein 4 [HE 4], interleukin-18 [IL-18], leptin, macrophage migration inhibitory factor [MIF], fibroblast growth factor 2 [FGF-2], insulin-like growth factor, osteopontin, prolactin) and the risk of malignancy indexes I and II (RMI-I and RMI-II) scores were obtained prior to surgery in 52 patients with ovarian tumours (37 malignant and 15 benign). ROC curves were built for each individual marker, for logistic regression models using all markers, and for models combining both biomarkers and RMI scores.. The model with nine biomarkers performed well (specificity 93%, sensitivity 84%) and was more reliable than the RMI-I or RMI-II alone. A regression model combining RMI-II and six of the biomarkers (CA 125, HE  4, IL-18, leptin, MIF, and FGF-2) allowed differentiation between the cancer and non-cancer cases in this pilot study.. The regression models using biomarkers combined with clinical scoring systems warrant further investigation to improve triage of patients with ovarian tumours to enhance utilization of resources and optimize patient care.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; CA-125 Antigen; Female; Fibroblast Growth Factor 2; Humans; Interleukin-18; Leptin; Macrophage Migration-Inhibitory Factors; Middle Aged; Osteopontin; Ovarian Neoplasms; Prolactin; Proteins; ROC Curve; Somatomedins; WAP Four-Disulfide Core Domain Protein 2; Young Adult

Mesothelioma and ovarian cancer have been reported to have a similar pathogenesis, and for this reason it was hypothesized that there may be biomarkers in common and possibly associated with benign pleural diseases caused by asbestos exposure.. Serum biomarkers including insulin-like growth factor-II (IGF-II), leptin, prolactin and vascular endothelial growth factor (VEGF) were measured in an observational study of subjects with benign asbestos-related pleural diseases (BARPD) (n=24) and healthy subjects with an asbestos exposure history (n=12).. Mean serum IGF-II and VEGF concentration in healthy subjects with a history of asbestos exposure were higher than those with BARPD. Mean serum concentrations of leptin and prolactin showed opposite trends when compared to IGF-II and VEGF concentrations among these groups.. The results suggest that IGF-II and VEGF concentrations are lower in BARPD, similar to studies of ovarian cancer. This finding warrants further investigation with malignant asbestos-related diseases.

Topics: Aged; Asbestos; Biomarkers, Tumor; Female; Humans; Insulin-Like Growth Factor II; Leptin; Male; Middle Aged; Ovarian Neoplasms; Pleural Diseases; Vascular Endothelial Growth Factor A

Previously, we demonstrated that leptin, a pleiotropic hormone produced by adipocytes, stimulates the growth of BG-1 ovarian cancer cells via the extracellular signal-regulated kinase signaling pathway. In this study, we further investigated the involvement of estrogen receptor (ER) pathway in the mechanism of leptin-induced ovarian cancer cell growth. Treatment with leptin (100 ng/ml) resulted in a significant increase in the cell growth of ERα-transfected OVCAR-3 and A2780 cells, whereas no significant difference was observed in ERβ-transfected cells. Downregulation of ERα using small interfering RNA completely reversed leptin-induced growth of BG-1 cells. Treatment with leptin resulted in ER transcriptional activation, i.e. nuclear localization of ER and increased expression of pS2, an estrogen-dependent gene. Luciferase reporter assay revealed that treatment of BG-1 cells with leptin (100 ng/ml) stimulated the expression of the reporter gene in the absence of estradiol (E2). To examine an involvement of Janus kinase 2/signal transducers and activators of transcription 3 (STAT-3) and phosphatidyl-inositol 3-kinase (PI3K)/Akt in leptin-induced pathway, we demonstrated that leptin increased phosphorylation of STAT-3 and Akt in BG-1 cells in a time- and dose-dependent manner. On the other hand, leptin-induced cell growth and ER transactivation were effectively blocked by specific STAT-3 inhibitor AG490 and, to a lesser extent, by PI3K inhibition. Further study with coimmunoprecipitation assay revealed that stimulation with leptin induced STAT-3 binding to ERα. Taken together, these results indicate that the stimulation of ovarian cancer cell growth by leptin involves, at least in part, ER transcriptional activation via the STAT-3 signaling pathways.

Topics: Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Fulvestrant; Humans; Leptin; Ovarian Neoplasms; Signal Transduction; STAT3 Transcription Factor

The progression of the neoplastic disease is characterized by specific alterations of energy metabolism and by symptoms like fatigue, anorexia, nausea, anaemia, immunodepression and poor performance status (PS). The main cause of these symptoms and metabolic abnormalities is the chronic action of proinflammatory cytokines released both by tumour and immune cells. The present study aimed to assess the relationship between markers of inflammation (C-Reactive Protein, Fibrinogen, proinflammatory cytokines) and energy metabolic status (BMI, leptin, oxidative stress) according to clinical parameters in 104 ovarian cancer patients at different stage and, moreover, to evaluate prospectively the changes of these parameters in accordance to tumour response in a subgroup of 70 advanced stage ovarian cancer patients. Advanced stage and poor PS were associated to high-grade inflammation and impaired energy metabolism. Among inflammatory mediators, interleukin (IL)-6 had a central role as predictive factor of leptin, reactive oxygen species and glutathione peroxidase. In turn, leptin considered the key marker of the nutritional status and energy metabolism, was independently determined from stage and IL-6, not only from BMI. Moreover, the evaluation of the changes of these parameters during the course of the neoplastic disease in the subgroup of advanced ovarian cancer patients clearly unveils the central role of IL-6 and leptin as early markers of the metabolic alterations and symptoms associated to disease progression in advanced stage ovarian cancer. Their assessment should be included in monitoring disease outcome, especially when cancer is no longer curable and quality of life becomes the primary endpoint.

Topics: Adult; Aged; Aged, 80 and over; Energy Metabolism; Female; Gene Expression Regulation, Neoplastic; Glutathione Peroxidase; Humans; Inflammation; Interleukin-6; Leptin; Middle Aged; Ovarian Neoplasms; Reactive Oxygen Species; Treatment Outcome

Recent epidemiological studies have suggested that obesity is associated with ovarian cancer. Obesity hormone leptin and its receptor (Ob-R) contribute to tumor development by enhancing cell growth and survival. This study was design to investigate the prevalence of leptin and Ob-R in Middle Eastern epithelial ovarian cancer (EOC) and to analyze the role of leptin and the mechanisms under its action in EOC tissue sample and cell lines.. The expression of leptin and Ob-R was examined by immunohistochemistry in a tissue microarray of 156 EOC samples. Proliferation of EOC cells in response to leptin was assessed by MTT assays, and its anti-apoptotic effects were determined by flow cytometry. Effect of leptin on PI3K/AKT signaling pathway was further determined by western blotting.. In clinical samples, Ob-R overexpression was seen in 59.2% EOCs and was significantly associated with poor progression free survival (p = 0.0032). Furthermore, Ob-R expression was associated with anti apoptotic proteins Bcl-XL (p = 0.0035) and XIAP (p = 0.0001). In vitro analysis using EOC cell lines showed that leptin stimulated cell proliferation and inhibits apoptosis via activation of PI3K/AKT signaling pathway. Inhibition of PI3K activity by LY294002, a specific inhibitor of PI3-kinase abrogated leptin mediated PI3K/AKT signaling. Gene silencing of Ob-R with Ob-R siRNA in EOC cells resulted in down regulation of phospho-AKT and its down stream targets.. Our findings have potential clinical implication for EOC development and progression.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Culture Media, Serum-Free; Disease Progression; Dose-Response Relationship, Drug; Epithelium; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leptin; Middle Aged; Middle East; Oncogene Protein v-akt; Outcome Assessment, Health Care; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Receptors, Leptin; RNA Interference; Signal Transduction; Tissue Array Analysis

The initial levels of soluble Fas antigen (sFas), leptin, and vascular endothelium growth factor (VEGF) were measured in the sera of 100 patients with ovarian cancer and benign tumors and in 60 healthy women aged 28-65 years. Serum levels of sFas and VEGF were elevated in the total group of patients with ovarian tumors, while leptin levels were the same as in healthy women. The studied parameters did not depend on the age of patients and healthy women. The levels of sFas and leptin were virtually the same in benign and malignant ovarian tumors, while VEGF concentration was higher in patients with ovarian cancer. The mean serum levels of sFas, VEGF, and leptin in patients with poorly and moderately differentiated serous ovarian cancer were 2-fold higher than in well-differentiated tumors (p<0.05), while serum concentrations of sFas and leptin increased with the disease stage progress in patients with ovarian cancer (p<0.05). According to the data of unifactorial analysis, the increase in serum levels of sFas and VEGF in ovarian cancer patients correlated with short duration of the relapse-free period. Multifactorial analysis showed that the disease stage (p=0.006), presence of ascites (p=0.03), VEGF concentration (p=0.02), and the sFas/leptin coefficient (p=0.045) are highly significant independent factors for predicting the relapse-free survival of patients with serous ovarian cancer.

Topics: Adult; Aged; Biomarkers, Tumor; fas Receptor; Female; Humans; Leptin; Middle Aged; Ovarian Neoplasms; Vascular Endothelial Growth Factor A

an attempt to determine the value of the simultaneous quantization of osteopontin (OPN), insulin-growth factor II (IGF II), leptin, prolactin and CA 125 for early detection of ovarian cancer.. Prospective study of 69 women including: 15 females with ovarian cancer; 33 females with benign ovarian neoplasm; 21 disease-free females; The levels of IGF II, prolactin, leptin and CA 125 were determined in serum, while the level of OPN was checked in plasma.. The concentrations of IGF II, leptin and prolactin do not let us distinguish among disease-free females, females with ovarian cancer and those with benign ovarian neoplasms on the basis of biochemical markers. The comparison of OPN and CA 125 levels showed significant differences in the concentrations of the biomarkers between disease-free females and females with ovarian cancer, as well as between females with benign ovarian neoplasms and females with ovarian cancer. The ROC curves for two groups: disease-free females and females with ovarian cancer, proved the diagnostic value of OPN and CA 125.. The simultaneous quantization of OPN, IGF II leptin and prolactin has not been proved useful for the early detection of ovarian cancer. Statistically significant increase of OPN & CA 125 levels was noted in case of women with ovarian cancer diagnosed through microscopic examination. The analysis of ROC curves showed comparable diagnostic usefulness of both markers. Quantization of OPN may have an additional value for treatment monitoring of women diagnosed with ovarian cancer but with concentration of CA 125 within the reference value.

Topics: Adult; Biomarkers, Tumor; CA-125 Antigen; Early Diagnosis; Female; Humans; Insulin-Like Growth Factor II; Leptin; Middle Aged; Osteopontin; Ovarian Neoplasms; Poland; Prolactin; Prospective Studies; Reference Values; ROC Curve; Sensitivity and Specificity

Early detection would significantly decrease the mortality rate of ovarian cancer. In this study, we characterize and validate the combination of six serum biomarkers that discriminate between disease-free and ovarian cancer patients with high efficiency.. We analyzed 362 healthy controls and 156 newly diagnosed ovarian cancer patients. Concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125 were determined using a multiplex, bead-based, immunoassay system. All six markers were evaluated in a training set (181 samples from the control group and 113 samples from OC patients) and a test set (181 sample control group and 43 ovarian cancer).. Multiplex and ELISA exhibited the same pattern of expression for all the biomarkers. None of the biomarkers by themselves were good enough to differentiate healthy versus cancer cells. However, the combination of the six markers provided a better differentiation than CA-125. Four models with <2% classification error in training sets all had significant improvement (sensitivity 84%-98% at specificity 95%) over CA-125 (sensitivity 72% at specificity 95%) in the test set. The chosen model correctly classified 221 out of 224 specimens in the test set, with a classification accuracy of 98.7%.. We describe the first blood biomarker test with a sensitivity of 95.3% and a specificity of 99.4% for the detection of ovarian cancer. Six markers provided a significant improvement over CA-125 alone for ovarian cancer detection. Validation was performed with a blinded cohort. This novel multiplex platform has the potential for efficient screening in patients who are at high risk for ovarian cancer.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Biomarkers, Tumor; CA-125 Antigen; Cytokines; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; False Positive Reactions; Female; Growth Differentiation Factor 15; Humans; Insulin-Like Growth Factor II; Leptin; Middle Aged; Osteopontin; Ovarian Neoplasms; Prolactin; Sensitivity and Specificity

The aims of the present study were to determine the serum concentrations of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and leptin and insulin resistance in benign and malignant epithelial ovarian tumors, and to discuss the use of these markers in benign-malignant tumor differentiation.. Forty-seven postmenopausal women with ovarian tumor and 31 age-matched, postmenopausal, healthy controls were included in this study. Insulin resistance index by homeostasis model assessment (HOMA score) and fasting blood glucose (FBG), serum IGF-I, IGFBP-3, leptin and CA-125 concentrations were determined in all patients preoperatively. The results were evaluated according to postoperative histopathology results.. According to postoperative histopathology results, the patients were divided into malignant (n = 23), benign (n = 24) and control (n = 31) groups. There were no differences among the groups in relation to age, body mass index, FBG and HOMA score (p > 0.05). Serum concentrations of CA-125 were elevated in the malignant group compared with the benign ovarian tumor and control groups (p < 0.05). In contrast, serum IGF-I concentrations were significantly decreased in patients with malignant and benign ovarian tumors compared with controls (p < 0.05). Serum IGFBP-3 concentrations were also found to be lower in women with malignant ovarian tumors than in women with benign tumors (p < 0.05). Serum leptin did not differ among patients with malignant-benign tumors and controls (p > 0.05).. Serum leptin and HOMA score have not been found to be valid indicators in ovarian tumors. However, the present data suggest that low concentrations of IGF-I and IGFBP-3 could be a reliable marker to differentiate benign from malignant ovarian tumors. Further experimental studies are warranted to understand the impact of the IGF-I system in ovarian carcinogenesis.

Topics: Biomarkers, Tumor; CA-125 Antigen; Female; Homeostasis; Humans; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Postmenopause

Hyperandrogenism in postmenopausal women is due to ovarian hyperthecosis or an androgen-secreting ovarian/adrenal tumor. Making the correct diagnosis might be complicated due to the possible existence of an adrenal neoplasm secreting testosterone only, ectopic ovarian tissue or ectopic luteinizing hormone/human chorionic gonadotropin receptors in the adrenals, as well as the relatively low sensitivity of imaging techniques (computed tomography, magnetic resonance imaging) and vein catheterization for this type of pathology. We present the case of an obese postmenopausal woman with metabolic syndrome, hyperandrogenism (high testosterone levels, suppressed gonadotropins), adrenal macronodular hyperplasia and Leydig-cell ovarian tumor. At presentation she had low leptin levels despite high body fat content. After a catheter study left adrenalectomy was carried out but hyperandrogenism persisted. Then, bilateral oophorectomy with hysterectomy was performed and a small Leydig-cell tumor was found in the left ovary. Postoperatively, testosterone and gonadotropin levels were normal (postmenopausal) and leptin level became elevated without change in body mass index or body fat content. In conclusion, we speculate that low leptin levels in obese hyperandrogenic women might be a marker for androgen-secreting tumors.

Topics: Adrenal Glands; Alopecia; Biomarkers; Female; Hirsutism; Humans; Hyperandrogenism; Hyperplasia; Leptin; Leydig Cell Tumor; Metabolic Syndrome; Middle Aged; Obesity; Ovarian Neoplasms

Leptin, a secreted protein of the ob gene by white adipose tissue, plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic breast cancer cells. However, a potential role of leptin as an endocrine regulator is unknown in ovarian cancer. In the present study, we investigated the expression of leptin receptors in immortalized ovarian surface epithelium (IOSE) and ovarian cancer cell lines, and potential effect of leptin on the cell growth and activation of mitogen-activated protein kinases (MAPKs) in the BG-1 ovarian cancer cell line. Both short and long isoforms of leptin receptors are expressed in IOSE-80PC (a post-crisis line), BG-1, OVCAR-3, and SKOV-3 cells. In addition, treatment with leptin resulted in the growth stimulation of BG-1 cells, an activation of ERK1/2 and inhibition of constitutive phosphorylation of p38 MAPK. These results suggest that further studies are necessary to validate whether leptin may be a potential regulator for ovarian cancer.

Topics: Cell Division; Cell Line, Tumor; Enzyme Activation; Female; Humans; Leptin; Mitogen-Activated Protein Kinases; Ovarian Neoplasms; Phosphorylation; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Signal Transduction

Anemia occurs in more than 30% of patients with epithelial ovarian cancer before any surgery. High levels of proinflammatory cytokines and increased oxidative stress may contribute to the development of cancer-related anemia. We assessed a population of previously untreated patients with advanced epithelial ovarian cancer to evaluate whether there was a correlation between hemoglobin (Hb) and parameters of inflammation and oxidative stress, stage of disease, and performance status (PS). In 91 patients with epithelial ovarian cancer and 95 healthy women matched for age, weight, and height, levels of Hb, C-reactive protein (CRP), fibrinogen (Fbg), proinflammatory cytokines, leptin, reactive oxygen species (ROS), and antioxidant enzymes were assessed at diagnosis before treatment. The correlations between Hb, parameters of inflammation and oxidative stress, stage, and PS were evaluated. Hb levels were lower in patients with advanced epithelial ovarian cancer than in control subjects and inversely related to stage and PS. Hb negatively correlated with CRP, Fbg, interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), and ROS, and positively correlated with leptin and glutathione peroxidase (GPx). Multivariate regression analysis showed that stage and IL-6 were independent factors determining Hb values. This evidence suggests that anemia in epithelial ovarian cancer is common and its presence is related to stage of disease and markers of inflammation.

Topics: Aged; Aged, 80 and over; Anemia; Biomarkers; C-Reactive Protein; Epithelial Cells; Erythrocyte Count; Female; Ferritins; Fibrinogen; Glutathione Peroxidase; Hemoglobins; Humans; Interleukin-1; Interleukin-6; Iron; Leptin; Middle Aged; Ovarian Neoplasms; Reactive Oxygen Species; Reticulocyte Count; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Early diagnosis of epithelial ovarian cancer (EOC) would significantly decrease the morbidity and mortality from this disease but is difficult in the absence of physical symptoms. Here, we report a blood test, based on the simultaneous quantization of four analytes (leptin, prolactin, osteopontin, and insulin-like growth factor-II), that can discriminate between disease-free and EOC patients, including patients diagnosed with stage I and II disease, with high efficiency (95%). Microarray analysis was used initially to determine the levels of 169 proteins in serum from 28 healthy women, 18 women newly diagnosed with EOC, and 40 women with recurrent disease. Evaluation of proteins that showed significant differences in expression between controls and cancer patients by ELISA assays yielded the four analytes. These four proteins then were evaluated in a blind cross-validation study by using an additional 106 healthy females and 100 patients with EOC (24 stage I/II and 76 stage III/IV). Upon sample decoding, the results were analyzed by using three different classification algorithms and a binary code methodology. The four-analyte test was further validated in a blind binary code study by using 40 additional serum samples from normal and EOC cancer patients. No single protein could completely distinguish the cancer group from the healthy controls. However, the combination of the four analytes exhibited the following: sensitivity 95%, positive predictive value (PPV) 95%, specificity 95%, and negative predictive value (NPV) 94%, a considerable improvement on current methodology.

Topics: Aged; Analysis of Variance; Biomarkers, Tumor; Blood Proteins; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; Female; Humans; Insulin-Like Growth Factor II; Leptin; Microarray Analysis; Middle Aged; Neoplasms, Glandular and Epithelial; Osteopontin; Ovarian Neoplasms; Prolactin; Proteins; Sensitivity and Specificity; Sialoglycoproteins

Leptin is a hormone involved in the regulation of body weight and sexual maturation. We previously reported that cancer cachexia was associated with reduced or normal levels of leptin. Here we investigate whether leptin levels are related to cachetic or hormonal status. Circulating leptin and its mRNA from adipose tissue were measured in 87 patients with gynaecological and breast cancers and related to tumour, cachexia and hormonal markers. We found that leptin protein increased in patients with these tumours due to higher mRNA levels. In patients with ovarian cancer, the increased leptin levels were associated with higher circulating follicle-stimulating hormone (FSH). The higher leptin concentrations in patients with endometrial and portio tumours were related to an increase in tissue estrogen receptor (ER) and progesterone receptor (PGR) and, only in the postmenopause, to an increase in circulating estradiol. Patients with breast cancer showed enhanced blood plasma concentrations of progesterone and estradiol, and enhanced tissue levels of ER and PGR associated with increased leptin levels. The data from the present study indicate that, in gynaecological and breast cancers, leptin is related to hormonal status but not to cachexia. We suggest that leptin stimulates the production of sexual hormones, important risk factors for these tumours, and we propose leptin as a novel prognostic marker.

Topics: Adipocytes; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Cachexia; Case-Control Studies; Female; Humans; Leptin; Neoplastic Cells, Circulating; Ovarian Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Uterine Neoplasms

One of the factors that predicts serum leptin levels is gender. It has been shown that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. We had the opportunity to examine the effects of acute and chronic changes in serum testosterone levels on serum leptin concentrations in two virilized females harbouring testosterone-secreting ovarian tumours, before and after curative surgery. Chronically elevated basal testosterone levels (46 nmol/l) were associated with suppressed serum leptin levels (1.46 microg/l and 2.56 microg/l) vs. 12 age- and BMI-matched healthy subjects 9.89 +/- 0.64 microg/l. Leptin levels were determined from pooled serum samples assayed by commercial radioimmunoassay. High testosterone levels abolished the well known sexual dimorphism of serum leptin levels. Two weeks after curative resection of these tumours serum leptin levels were unaltered and started to increase progressively after one month. One patient received parenteral conjugated oestrogens while the other resumed spontaneous menstrual cycles. Three months after curative surgery obvious changes in body composition were registered (DEXA). Six months later further rise in serum leptin concentrations occurred without further changes in body composition. In conclusion, leptin levels did not change in spite of rapid changes in the steroid milieu, but in the long term increase in body fat stores, new steroid milieu and maybe other factors are important determining factors of serum leptin levels.

Topics: Adult; Body Composition; Case-Control Studies; Female; Humans; Leptin; Leydig Cell Tumor; Middle Aged; Ovarian Neoplasms; Postoperative Period; Sex Characteristics; Testosterone; Virilism