Functional evidence for two distinct mechanisms of action of progesterone and selective progesterone receptor modulator on uterine leiomyomas.

OBJECTIVE: To study the specific mechanisms through which progesterone and selective progesterone receptor modulators impact the growth, synthesis, and accumulation of the extracellular matrix in uterine leiomyomas. DESIGN: Laboratory study. SETTING: Academic Research Institutions. PATIENTS (S): This study involved reproductive-age women diagnosed with infertility associated uterine leiomyomas who underwent myomectomy either after selective progesterone receptor modulator ulipristal acetate (UA) treatment or without any pharmacological pretreatment. Control samples included healthy myometrium tissue (n = 100). Specimens were obtained from the Department of Reproduction and Gynecological Endocrinology and Biobank, Medical University of Bialystok, Poland. INTERVENTIONS: Daily (5 mg/d) UA treated for 2 months (n = 100) and untreated (n = 150) patients with uterine leiomyomas or normal healthy myometrium (n = 100) tissue samples immediately after surgery were collected for transcriptional analysis and assessments. MAIN OUTCOME MEASURES: Progesterone-induced activation of the signaling pathways related to uterine leiomyomas extracellular matrix synthesis, deposition, and growth, as well as the expression profile of progesterone receptors in uterine leiomyomas, were assessed. RESULTS: The results indicated that progesterone activated the transforming growth factor-ß and SMAD3 signaling pathways and promoted proliferation, growth, and extracellular matrix remodeling in uterine leiomyomas by up-regulating SMAD3, transforming growth factor-ß (TGF-ß) receptor type 1 and II, Ras homolog A, vascular endothelial growth factor, or increasing the fibrosis-related gene collagen, type I, ɑ-1, and procollagen, type I, ɑ-1 production. In contrast, UA had inhibitory effects on these processes. The study also showed that both nuclear and membrane progesterone receptors play distinct roles in uterine leiomyoma pathobiology. CONCLUSIONS: We showed that both nuclear and membrane progesterone receptors were relevant in the treatment of uterine leiomyomas, especially when combined with selective progesterone receptor modulators. Novel therapeutic approaches combining selective progesterone receptor modulators with or without direct and indirect extracellular matrix targeting through selected specifically TGF-ß and SMAD3 (SMAD3, TGF-ß receptor types 1 and II, Ras homolog A, vascular endothelial growth factor, collagen, type I, ɑ-1) signaling pathways could therefore be a treatment option for uterine leiomyomas.

Progesterone signaling in uterine leiomyoma biology: Implications for potential targeted therapy.

Uterine leiomyomas (ULs) are the most common benign smooth muscle cell steroid-dependent tumors that occur in women of reproductive age. Progesterone (P4) is a major hormone that promotes the ULs development and growth. P4 action in ULs is mediated mainly by its nuclear progesterone receptors (PGRs), although rapid non-genomic responses have also been observed. Data on the membrane progesterone receptors (mPRs) regulated signaling pathways in ULs in the available literature is still very limited. One of the essential characteristics of ULs is the excessive production of extracellular matrix (ECM). P4 has been shown to stimulate ECM production and collagen synthesis in ULs. Recent research demonstrated that, despite their benign nature, ULs may present with abnormal vasculature. P4 has been shown to regulate angiogenesis in ULs through the upregulation of vascular endothelial growth factor (VEGF) and by controlling the secretion of permeability factors. This review summarizes the key findings regarding the role of PGRs and mPRs in ULs, especially highlighting the potential ECM and angiogenesis modulation by P4. An increased understanding of this mechanistic role of nuclear and specifically mPRs in the biology of P4-modulated ECM and angiogenesis in the growth of ULs could turn out to be fundamental for developing effective targeted therapies for ULs.

New Insights on the Progesterone (P4) and PGRMC1/NENF Complex Interactions in Colorectal Cancer Progression.

The literature data regarding the risk of colorectal cancer (CRC) in the context of hormone therapy (HT), including both estrogen-progestogen combinations and estrogen alone, are inconclusive. The precise relationship underlying the action of progesterone (P4) and progesterone receptors in CRC has yet to be determined. We characterized the expression profiles of both nuclear and membrane progesterone receptors and their potential cofactors in CRC tissues. Additionally, we analyzed the P4 and NENF treatment effects on the cell proliferation and invasion of DLD-1 and HT-29 colorectal cancer cells. We observed a weak expression of the nuclear P4 receptor (PGR), but an abundant expression of the P4 receptor membrane component 1 (PGRMC1) and neuron-derived neurotrophic factor (NENF) in the CRC tissues. P4 treatment stimulated the proliferation of the DLD-1 and HT-29 CRC cells. The co-treatment of P4 and NENF significantly increased the invasiveness of the DLD-1 and HT-29 cells. A functional analysis revealed that these effects were dependent on PGRMC1. AN immunocytochemical analysis demonstrated a cytoplasmic co-localization of PGRMC1 and NENF in the CRC cells. Moreover, the concentration of serum NENF was significantly higher in CRC patients, and P4 treatment significantly increased the release of NENF in the DLD-1 cells. P4 or NENF treatment also significantly increased the IL-8 release in the DLD-1 cells. Our data may provide novel insights into the action of P4 and PGRMC1/NENF in CRC progression, where NENF may act as a potential PGRMC1 co-activator in non-classical P4 signaling. Furthermore, NENF, as a secreted protein, potentially could serve as a promising circulating biomarker candidate for distinguishing between colorectal cancer patients and healthy individuals, although large-scale extensive studies are needed to establish this.

Functional Implications of Estrogen and Progesterone Receptors Expression in Adenomyosis, Potential Targets for Endocrinological Therapy.

Adenomyosis is a common gynaecological disease associated with the presence of endometrial lesions in the uterine myometrium. Estrogens have been proven to be the crucial hormones driving the growth of adenomyosis. Little is known about the distinct mechanisms of progesterone action in adenomyosis. Hence, in this study, we decided to characterize the expression of all nuclear and membrane estrogen and progesterone receptors. Additionally, as a functional investigation, we monitored prolactin production and cell proliferation after estradiol and progesterone treatments. We confirmed the presence of all nuclear and membrane estrogen and progesterone receptors in adenomyotic lesions at gene and protein levels. The expression of membrane progesterone receptors α and ß (mPRα, mPRß) as well as estrogen receptor ß (ERß) was upregulated in adenomyosis compared to normal myometrium. Estradiol significantly increased adenomyotic cell proliferation. Progesterone and cAMP upregulated prolactin secretion in adenomyosis in the same pattern as in the normal endometrium. In the present study, we showed the functional link between estradiol action and adenomyotic cell proliferation, as well as progesterone and prolactin production. Our findings provide novel insights into the sex steroid receptor expression pattern and potential regulated pathways in adenomyosis, suggesting that all receptors play an important role in adenomyosis pathophysiology.

Novel expression of zona pellucida 3 protein in normal testis; potential functional implications.

The expression of the zona pellucida glycoprotein 3 (ZP3), originally thought to be specific for oocytes, was recently extended to ovarian, prostate, colorectal and lung cancers. Earlier successful ZP3 immunization of a transgenic mouse model carrying a ZP3 positive ovarian tumor emphasized the suitability of ZP3 for cancer immunotherapy. This study was carried out to determine whether any other normal tissues besides the ovary in healthy human and mouse tissues may express ZP3, considered important to exclude off-target effects of ZP3 cancer immunotherapy. Strong ZP3 expression was found in normal human and mouse testis. ZP3 protein and mRNA transcripts were localized in spermatogonia, spermatocytes and round and elongated spermatids of both human and mouse testis, as well as in a mouse spermatogonial cell line, but absent in testicular Sertoli, Leydig, spermatogonial stem and progenitor cells. All other normal human and mouse tissues were ZP3 negative. This surprising testicular ZP3 expression has implications for the development of ZP3 cancer immunotherapies, and it also alludes to the potential of using ZP3 as a target for the development of a male immunocontraceptive.

Two Concurrent Cancers in a 19-Year-Old Patient: Yolk Sac Ovarian Tumor and Metastatic Gastrointestinal Tract Malignancy-Case Report.

BACKGROUND: Two concurrent malignancies present in a young person is an extremely rare condition. Diagnoses of gastric cancer primarily concern older patients. There are very few reports of concomitant Krukenberg tumor and germ-cell ovarian malignancy. CASE: A 19-year-old girl was admitted to the gynecologic oncology department with symptoms of advanced malignancy. Radiological imaging revealed disseminated neoplastic disease with bulky adnexal tumors. Cytoreductive surgery was performed, achieving no visible disease (T = 0 cm). The final pathology report confirmed metastatic mixed adenoneuroendocrine carcinoma (MANEC) in both ovaries, originating from the gastrointestinal tract. Moreover, the primary germ cell yolk sac tumor was found in the left ovary. CONCLUSION: In cases of concomitant gastric and ovarian tumors, metastatic disease (Krukenberg tumor) should be considered in the differential diagnosis. This concerns even adolescent patients. In particular cases, including tumors with germ cell components, primary debulking surgery is crucial for prognosis.

Mifepristone Treatment Promotes Testicular Leydig Cell Tumor Progression in Transgenic Mice.

The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Traceable/absent classical Pgr or nonclassical membrane PRs α, ß, γ and Pgrmc2, but abundant membrane Pgrmc1 expression, was found in LCTs. MF did not activate glucocorticoid or androgen receptors in LCTs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Accordingly, MF and P4 induced PGRMC1 translocation into the nucleus and thereby stimulated the release of TGFß1 in LCT cells. MF and P4 treatments upregulated Tgfbr1, Tgfbr2, and Alk1 expression and stimulated TGFß1 release in LCT cells. Our findings provide novel mechanistic insights into the action of MF as a membrane PR agonist that promotes LCT growth through PGRMC1 and the alternative TGFß1 signaling pathway.

The effect of interleukin 6 deficiency on myocardial signal transduction pathways activation induced by bacterial lipopolysaccharide in young and old mice.

PURPOSE: Exaggerated release of proinflammatory mediators during sepsis contributes to inadequate vasodilatation and depressed myocardial contractility, which lead to development of shock and circulatory collapse. The aim of the study was to evaluate the effect of IL-6 and aging on activation of intracellular signaling pathways in the myocardium induced by bacterial lipopolysaccharide (LPS) administration. MATERIAL/METHODS: LPS was injected intraperitoneally to male 3- and 24-month old mice with systemic IL-6 gene knock-out (IL-6KO) and the reference strain (WT). LPS was given intraperitoneally in single low (0.1 mg/kg) or high (10 mg/kg) dose, or in two doses (0.1 + 10 mg/kg) with 24-h delay. The expression and phosphorylation of STAT3, ERK1/2, Akt1/2/3 proteins in the left ventricular myocardium was evaluated after 24 h using Western blotting. RESULTS: Low LPS dose induced higher STAT3 phosphorylation only in old IL-6KO mice, not affecting ERK1/2 and Akt1/2/3 phosphorylation in any group. High LPS dose upregulated STAT3 phosphorylation similarly in all groups, reduced ERK1/2 expression in young WT mice and upregulated Akt1/2/3 expression and phosphorylation in young IL-6KO mice. Pretreatment with low LPS dose attenuated phosphorylation of STAT3 in both old groups and phosphorylation of Akt1/2/3 in young IL-6KO group. Two-dose approach also significantly potentiated ERK1/2 phosphorylation in both old groups. CONCLUSIONS: Obtained results show that IL-6 deficiency alters the activity of intracellular signaling pathways: JAK/STAT in old and Akt in young LPS-treated mice. This may indicate that lack of IL-6 attenuates Akt-related cytoprotective effect of pretreatment with low LPS dose in young but not in aged animals.

Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression.

BACKGROUND: Recent clinical trials on ovarian cancer with mifepristone (MF) have failed, despite in vitro findings on its strong progesterone (P4) antagonist function. METHODS: Ovarian cancer human and murine cell lines, cultured high-grade human primary epithelial ovarian cancer (HG-hOEC) cells and their explants; as well as in vivo transgenic mice possessing ovarian cancer were used to assess the molecular mechanism underlying mifepristone (MF) agonistic actions in ovarian cancer progression. FINDINGS: Herein, we show that ovarian cancer cells express traceable/no nuclear P4 receptor (PGR), but abundantly P4 receptor membrane component 1 (PGRMC1). MF significantly stimulated ovarian cancer cell migration, proliferation and growth in vivo, and the translocation of PGRMC1 into the nucleus of cancer cells; the effects inhibited by PGRMC1 inhibitor. The beneficial antitumor effect of high-doses MF could not be achieved in human cancer tissue, and the low tissue concentrations achieved with the therapeutic doses only promoted the growth of ovarian cancers. INTERPRETATION: Our results indicate that treatment of ovarian cancer with MF and P4 may induce similar adverse agonistic effects in the absence of classical nuclear PGRs in ovarian cancer. The blockage of PGRMC1 activity may provide a novel treatment strategy for ovarian cancer. FUND: This work was supported by grants from the National Science Centre, Poland (2013/09/N/NZ5/01831 to DP-T; 2012/05/B/NZ5/01867 to MC), Academy of Finland (254366 to NAR), Moikoinen Cancer Research Foundation (to NAR) and EU PARP Cluster grant (UDA-POIG.05.01.00-005/12-00/NCREMFP to SW).

Interleukin 6 modulates PPARα and PGC-1α and is involved in high-fat diet induced cardiac lipotoxicity in mouse.

BACKGROUND: Interleukin 6 (IL-6) may be involved in regulation of cardiac lipid metabolism and mitochondrial function through its influence on peroxisome proliferator-activated receptors (PPARs). In this study we evaluated the impact of the physiological level of IL-6 on the expression of PPARα and PGC-1α in the heart and the effect of lack of this cytokine on high-fat diet (HFD) induced lipotoxicity. METHODS: Male C57BL6/J wild type (WT) and IL-6 knock-out (IL-6KO) mice were used. 20 animals of each genotype were fed with HFD for 15-18weeks. Cardiac function was assessed using echocardiography and cardiomyocyte ultrastructure was examined using electron microscopy. QT-PCR and Western blotting were applied to estimate the expression of PPARα and PGC-1α at the transcriptional and protein levels. RESULTS: At baseline WT and IL-6KO mice had similar size and function of the left ventricle. HFD induced similar left ventricular hypertrophic response in both groups without causing heart failure, but only WT animals had increased resting ejection fraction of the LV. Ultrastructure of HFD groups showed markers of lipotoxicity, that were more pronounced in IL-6KO group. In basal conditions IL-6KO animals had lower PPARα and similar PGC-1α expression as compared to WT. HFD induced downregulation of both PPARα and PGC-1α in WT animals, while in IL-6KO mice this effect was constrained. CONCLUSION: IL-6 is involved in basal regulation of PPARα and PGC-1α expression in cardiomyocytes. The lack of this cytokine promotes high-fat diet induced lipotoxicity but without overt manifestations of cardiac failure.

Functional Expression of FSH Receptor in Endometriotic Lesions.

CONTEXT: FSH receptor (FSHR), besides being expressed in gonads, is also expressed in some extragonadal tissues at low levels. OBJECTIVE: We examined the functional expression of FSHR in different types of endometriotic lesions. DESIGN: Extensive studies were carried out to detect functional FSHR expression and FSH-stimulated estrogen production in ovarian endometriomas and recto-vaginal endometriotic nodules (RVEN). Normal endometrium, ovary, and myometrium tissues from nonpregnant cycling women served as controls. SETTINGS: This laboratory-based study was carried out on tissue specimens from patients with endometriosis and healthy donors. RESULTS: Endometriotic lesions and normal secretory-phase endometrium showed FSHR expression at both mRNA and protein level. RVEN and ovarian endometrioma demonstrated up-regulated CYP19A1, dependent on the activation of CYP19A1 proximal promoter II. Estrogen receptor-ß (ESR2) expression was significantly increased in RVEN vs normal endometrium. Recombinant human FSH stimulation of RVEN explants significantly increased estradiol production and CYP19A1 and ESR2 expression. FSHR was up-regulated in recombinant human FSH-stimulated endometrial and decidualized stromal cells with increased CYP19A1 expression. CONCLUSIONS: We described a novel functional FSHR expression, where FSH-stimulated CYP19A1 expression and estrogen production in RVEN are demonstrated. This locally FSH-induced estrogen production may contribute to the pathology, development, progression, and severity of RVEN.

Clinical evaluation of photodynamic therapy efficacy in the treatment of oral leukoplakia.

BACKGROUND: The aim of the study was clinical evaluation of photodynamic therapy efficacy in the treatment of oral leukoplakia lesions. METHODS: Twenty-three consecutive patients aged 21-79 were included to the study. In all patients 44 homogeneous, flat leukoplakia lesions were clinically diagnosed and confirmed histopathologically. Photodynamic therapy was performed with the use of Photolon(®) photosensitizer, containing 20% Chlorine-e6 and 10% dimethyl sulfoxide and a semiconductor laser, with power up to 300mW and a wavelength of 660nm. Ten illumination sessions were conducted with the use of superficial light energy density of 90J/cm(2). RESULTS: At baseline the mean size of leukoplakia lesion was 6.5±5.10cm(2) while after photodynamic therapy 3±2.99cm(2). Significant reduction (on average by 53.8%) of leukoplakia lesions sizes was observed after therapy. Twelve (27.27%) lesions had been completely cured, 22 (50%) partially cured, although 10 (22.73%) lasted unchanged. The efficacy of PTD was comparable in women and men irrespective of age. There have been no adverse site effects during therapy noted. CONCLUSIONS: Within the limits of the study it can be concluded that photodynamic therapy with the use of Chlorine-e6 can lead to considerable reduction of oral leukoplakia lesions size thus may be useful in clinical practice. However there is a need of further studies on larger number of cases and longer follow-up time.

Evaluation of mast cells and hypoxia inducible factor-1 expression in meningiomas of various grades in correlation with peritumoral brain edema.

Meningiomas are common primary brain tumors. However, they are often complicated by significant peritumoral brain edema, which leads to surgery difficulties and prolonged hospitalization. The aim of this study was to evaluate the presence of mast cells and expression of hypoxia inducible factor-1 (HIF-1) in correlation with the grade of meningioma and presence of peritumoral brain edema. Immunohistochemistry was performed with specific antibodies against tryptase (mast cells) and HIF-1 in low grade meningiomas (estimated as G1) and high grade meningiomas (estimated as G2 or G3). Peritumoral brain edema observed in MRI was graded using Steinhoff classification. Tryptase expression was observed in 40.4 % low grade meningiomas and in 90 % high grade cases; HIF-1 in 55.7 % low grade and in 84 % high grade meningiomas. There was a statistically significant correlation between HIF-1 and tryptase expression in both groups (p = 0.003). Presence of peritumoral brain edema statistically correlated with tryptase (p = 0.001) and HIF-1 expression (p = 0.004). Mast cells as well as hypoxia are involved in meningioma progression, and may be associated with the formation of peritumoral brain edema leading to surgery complication and recovery. Therefore, they may be useful markers in predicting the clinical course of meningioma cases.

Clinical assessment of the efficacy of photodynamic therapy in the treatment of oral lichen planus.

The study objective was clinical assessment of the efficacy of photodynamic therapy (PDT) in the treatment of oral lichen planus (OLP). There were 23 patients aged 31-82 included in the study with oral lichen planus diagnosed clinically and histopathologically. In all patients photodynamic therapy was performed with the use of chlorin e6 (Photolon(®)), containing 20 % chlorin e6 and 10 % dimethyl sulfoxide as a photosensitizer. PDT was performed using a semiconductor laser, with power up to 300 mW and a wavelength of 660 nm. A series of illumination sessions was conducted with the use of superficial light energy density of 90 J/cm(2). Changes of lesion size were monitored at one, two, five, and ten PDT appointments from the series of ten according to the authors' own method. The sizes of clinical OLP lesions exposed to PDT were reduced significantly (on average by 55 %). The best effects were observed for the lesions on the lining mucosa (57.6 %). The therapy was statistically significantly less effective when masticatory mucosa was affected (reduction, 30.0 %). Due to substantial efficacy and noninvasiveness, PDT can be useful in the treatment of OLP lesions.

HIF-1 expression in retinal ganglion cells and optic nerve axons in glaucoma.

Glaucoma is a result of increased intraocular pressure leading to damage to retinal ganglion cells and optic nerve axons. The aim of this study was to evaluate HIF-1 expression in optic nerve axons and retinal ganglion cells in 42 eyes enucleated because of complete glaucoma compared to eyes removed because of injury.The immunohistochemical reaction was done and specimens were examined under a light microscope. 57% of cases presented HIF-1 expression in the optic nerve axons, and 52.3% in the retinal ganglion cells. 20 out of 42(47.6%) cases were HIF-1 positive both in the optic nerve axons and in the retinal ganglion cells, and the staining was evident mostly in the nuclear and perinuclear area. Our present results indicate that HIF-1 expression in hypoxic conditions in glaucoma might be a very crucial stage in damage to retinal ganglion cells and optic nerve axons, and might be a successful target for the implementation of neuroprotective drugs.

c-erbB-2 protein expression in astrocytic tumors of the brain.

BACKGROUND: Astrocytic tumors are the primary brain tumors, which often progress to glioblastoma, a highly malignant neoplasm of the central nervous system. There is much new data regarding to the formation and progression of these tumors; however, glioblastoma remains one of the most fatal neoplasms in humans. The aim of the study was to evaluate the role of c-erbB-2 protein expression in various groups of astrocytic tumors. MATERIAL/METHODS: 65 cases of astrocytic tumors were divided into 3 groups: diffuse astrocytoma (group I; n=17 cases), anaplastic astrocytoma (group II; n=23 cases) and glioblastoma (group III; n=25 cases). C-erbB-2 protein expression was estimated semiquantitatively on immunohistochemically stained tissue sections using antibodies against c-erbB-2 protein. Statistical analysis was performed in all examined groups. RESULTS: The c-erbB-2 protein expression was observed in 15 out of 17 cases (88.3%) in group I, 22 out of 25 cases (88%) cases in group II, and in 19 out of 23 cases (82.6%) in group III. There were no statistically significant differences between the examined groups. The strongest c-erbB-2 immunoexpression was observed in low grade astrocytomas (diffuse astrocytomas G2); in the glioblastoma group the c-erbB-2 protein expression was weak and 17.4% of cases were negative. CONCLUSIONS: C-erbB-2 protooncogene alteration is an early phenomenon in glial tumor development and progression.

The evaluation of human papillomavirus and p53 gene mutation in benign and malignant conjunctiva and eyelid lesions.

Papillomas and squamous cell carcinomas are the most common conjunctival and eyelid lesions. The etiology is still unclear and recently human papillomavirus infection and p53 gene mutation have been taken into consideration. The aim of our study was the evaluation of HPV DNApresence and p53 gene mutation in 45 benign and 38 malignant squamous lesions of the conjunctiva and eyelid. For HPV detection PCR-RFLP and immunohistochemical reaction were used; for p53 gene mutation PCR-SSCP was used. Only 8.8% papillomas, 9.1% squamous cell cancers and 3.7% basal cell cancers (using PCR-RFLP method) and 26.6% papillomas, 7.4% squamous cell cancers and 9.1% basal cell cancers (using immunohisto-chemical reaction) were HPV positive. p53 gene mutation was evaluated in 24.4% papillomas, 54.5% squamous cell cancers and 22.2% basal cell cancers; most commonly in 6 and 7 exon. Human papillomavirus infection, opposite to p53 gene mutation, is not a significant etiological factor of the benign and malignant conjunctival and eyelid lesions development.

Prognostic significance of smac/DIABLO in endometrioid endometrial cancer.

Apoptosis may occur via a death receptor-dependent or independent (mitochondrial) pathway. The mitochondrial pathway is regulated by small molecules, such as smac/Diablo, which activates caspase cascades. This study examined smac/DIABLO expression in 76 patients with endometrioid endometrial cancers. Presence of smac/DIABLO was quantified by Western blot analysis using nonfixed fresh frozen tissues. Its appearance was found in 55 (72%) of examined tumors. Smac/DIABLO expression significantly correlated with tumor grade (p<0.001). Patients with positive smac/DIABLO tumors had a longer disease-specific survival when compared with those with negative tumors in the 10-year follow-up (p=0.043). The study demonstrated that negative smac/DIABLO expression was a poor prognostic sign.

Tumor necrosis factor-alpha and its receptors in epithelial ovarian cancer.

The aim of the present study was to characterize the expression pattern of tumor necrosis factor (TNF)-alpha and its receptors (TNF-Rs) in the epithelial ovarian cancer (EOC) and compare these results with the outcome of 126 patients. Presence of TNF-alpha, TNFR-1 and TNFR-2 were studied by Western blotting and immunohistochemistry. The proportion of samples positive for TNF-alpha and TNF-R2 was higher in epithelial ovarian cancer patients than in benign ovarian diseases (p<0.001 and p=0.016, respectively). Immunostaining intensity of TNF-R2 were correlated with tumor stage (p<0.001) and with reduced mean survival time (MST) (p=0.002). The results of the present study suggested that tissue expression of TNF-R2 in epithelial ovarian cancer was correlated with the highest risk of cancer progression. Thus, the clinical value of activated TNF system in epithelial ovarian cancer needs to be further investigated.